CN1249748A - Small molecules useful in treatment of inflamatory disease - Google Patents

Small molecules useful in treatment of inflamatory disease Download PDF

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CN1249748A
CN1249748A CN98803012A CN98803012A CN1249748A CN 1249748 A CN1249748 A CN 1249748A CN 98803012 A CN98803012 A CN 98803012A CN 98803012 A CN98803012 A CN 98803012A CN 1249748 A CN1249748 A CN 1249748A
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carbon atom
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formula
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atom
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特伦斯·A·凯利
巴巴拉·J·博曼
利厄·L·弗赖伊
吴江平
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Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim Pharmaceuticals Inc
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Abstract

A method treating or preventing inflammatory and immune cell-mediated diseases by the administration of certain novel and known small molecules. Exemplary of the novel compounds are those of structural formulas (a), (b), (c), (d), (e) and (f).

Description

The small molecules that is used for the treatment of inflammatory disease
Invention field
The present invention relates generally to serial new small molecule, its synthetic method and their purposes in the treatment inflammatory disease.The invention still further relates to similarly, still is the purposes of compound known in the treatment inflammatory disease.
Background of invention
The research of crossing over last decade helps to illustrate the molecular phenomenon of keeping cells in vivo-cell interaction, especially the phenomenon that comprised in moving and activating of those cells in immunity system.Generally referring to Springer, T.Nature, 1990,346,425-434.Cell surface proteins, especially cell adhesion molecule (" CAMs ") and " white integrin (Leukointegrins) " comprise LAF-1, MAC-1 and gp150.95 (are called CD18/CD11a in the WHO term, CD18/CD11b and CD18/CD11c) correspondingly become the theme of drug research and exploitation, its objective is to prevent that white corpuscle is seeped into damage position and white corpuscle outward and moves to different targets.For example, think at present the indication composition white corpuscle of inflammatory response exosmose before, occur in the activation of the integrin of constitutive expression on the white corpuscle, then be the interaction that tight ligand/receptor takes place between the different cell-cell adhesion molecules (ICAMs) of integrin (for example LFA-1) and one or several design ICAM-1, ICAM-2, ICAM-3 or ICAM-4, described cell-cell adhesion molecule is expressed on vascular endothelial cell surface and other white corpuscle.CAMs is a kind of live body step in immune normal function with the interaction of white integrin.
Cytotoxicity that for example antigen presentation of immunologic process, T-are cell-mediated and white corpuscle exosmose all needs the cell adhesion that mediates by the interaction between ICAMs and the white integrin.Generally referring to Kishimoto, T.K.; Rothlein; R.R.Adv.Pharmacol.1994,25:117-138 and Diamond, M.; Springer, T. " current biological chemistry ", 1994,4,506-532.
People have differentiated one group of individuality, and it lacks the suitable expression of white integrin, are called as symptom (Anderson, the D.C. of " the white corpuscle adhesion lacks "; Deng the people, Fed.Proc.1985,44,2671-2677 and Anderson, people such as D.C., J.Infect.Dis.1985,152,668-689).These individualities be can not determine normal inflammation and/or immunne response, because its cell can not be adhered on the cell substrate.These data show when lymphocyte for want of the CD18 class the function adhesion molecule and can not adhere in normal mode the time, immune response is slowed down.Because patient LAD who lacks CD18 can not determine the fact of inflammatory response, think that the interactional antagonistic action of CD18, CD11/ICAM-1 also can reply by inflammation-inhibiting.
Confirmed that interactional antagonistic action can be by realizing at the medicine of one of two kinds of compositions between CAMs and the white integrin.Specifically, CAMs for example ICAM-1 or white integrin for example LFA-1 sealing by in these molecules one or two antibody and effectively inflammation-inhibiting reply.The external model of inflammation and antibody comprise antigen or mitogen inductive lymphopoiesis, lymphocytic homotypic aggregation, cell-mediated cytolysis and the antigen-specific inductive tolerance of T-to the immunne response of the inhibition of CAMs or white integrin.Research uses antibody at ICAM-1 or LFA-1 to carry out that research confirms in the body in the relevant body.For example the antibody at LFA-1 can prevent that the thyroid transplantation of mouse from repelling and prolonging survival (Gorski, the A. of heart allograft; " current immunology ", 1994,15,251-255).More obviously be that antibody at ICAM-1 has shown that for example kidney allograft repels and effect (Rothlein, the R.R. of rheumatoid arthritis to human body diseases in vivo as antiphlogiston; Scharschmidt, L. is in " adhesion molecule "; Wegner, C.D., Ed.; 1994,1-38, Cosimi, C.B.; Deng the people, " IMMUNOLOGY KEY WORDS INDEX, 1990,144,4604-4612 and Kavanaugh, A.; Deng the people, Arthritis Rheum.1994,37,992-1004) and at the antibody of LFA-1 verified bone marrow transplantation and the prevention kidney allograft early stage repulsion in immunosuppressive effect (Fischer, A.; Deng the people, Lancet, 1989,2,1058-1060 and Le Mauff, B.; Deng the people, " transplanting ", 1991,52,291-295).
The recombinant chou that has proved the ICAM-1 of soluble form can play ICAM-1 and the interactional inhibitor effect of LFA-1.The ICAM-1 of solubility plays the directed antagonist of CD18, CD11/ICAM-1 interaction on cell, and shown inhibition activity in the external model of immunne response, for example be mixed with lymphocyte responses, cytotoxic T cell is replied and inhibition activity (Becker, J.C. in the human body of the T of the diabetic that islet cell is replied cell proliferation; Deng the people, " IMMUNOLOGY KEY WORDS INDEX, 1993,151,7224 and Roep, B.O.; Deng the people, Lancet, 1994,343,1590).
Therefore, on the verified larger protein molecule that antagonistic action is arranged that CAMs is attached to white integrin of prior art reduce inflammation with usually relevant immunne response with the pathology of many autoimmunities or inflammatory disease in the treatment ability is arranged.But, as medicine protein, there is obvious defects, comprising can not oral administration and potential immunocompetence, and this activity limits the practicality of these molecule long term administrations.In addition, the preparation of protein-based medicine is normally expensive.
Have with the similar small molecules of ability that CAMs is attached to the larger protein molecule of white integrin be preferred medicine.But the small molecules that directly plays up to now, antagonistic action yet there are no report.
In influencing CAMs and the white interactional document of integrin, several small molecules have been described.In conjunction with in measuring, find that the natural product of separating has inhibition (Musza, L.L. at cell in vitro from the root of Trichilia rubra; Deng the people, Tetrahedrom, 1994,50,11369-11378).Also find serial molecule (Boschelli, D.H.; Deng people's " journal of medicinal chemistry ", 1994,37,717 and Boschelli, D.H.; Deng people's " journal of medicinal chemistry " 1995,38,4597-4614) in oppositely passive Arthus reaction (a kind of is the guidance model of the inflammation of feature with the neutrophil accumulation), have Orally active (Chang, Y.H.; Deng the people, Eur. " pharmacology magazine ", 1992,69,155-164).Find that also other a series of molecules have Orally active (Sanfilippo, P.J. in the delayed type hypersensitivity reaction of rat; Deng the people, " journal of medicinal chemistry ", 1995,38,1057-1059).All these molecules play nonspecific action, or the active effect that suppresses transcribing of ICAM-1 or play the white integrin of intercellular inhibition by unknown mechanisms with other protein.There is not a kind of molecular energy directly the interaction between CAMs and the Leukointegrins to be played antagonistic action.Because lack the special mechanism of potentiality, shortage selectivity and shortage effect, therefore, described small molecules can not satisfy the requirement of therepic use equally.
Based on the situation of prior art, can be clear that still need a kind of to the interact small molecules of treatment usefulness of CAMs and Leukointegrins with antagonistic ability.
The invention overview
First aspect of the present invention comprises by administration some novel and known small molecules with treatment or prevent inflammation and the method for the disease of immunocyte mediation.These compounds especially work by the combination of antagonism human body intercellular adhesion molecule (comprising for example ICAM-1, ICAM-2 and ICAM-3) dialogue integrin (comprising for example CD18/CD11a and CD18/CD11b) by suppressing the interaction of cell adhesion molecule.Second aspect of the present invention comprises the new small molecule with above-mentioned therapeutic activity.A third aspect of the present invention comprises the preparation method of these novel cpds.Last aspect of the present invention comprises pharmaceutical composition, and it contains above-claimed cpd, is suitable for preventing or treating the disease of inflammation and immunocyte mediation.Detailed description of the present invention
In a first aspect of the present invention, comprise by some novel and known formula I small molecules of administration or its pharmacologically acceptable salt method with the disease of treatment or preventing inflammation and immunocyte mediation
Wherein:
Y is oxygen or sulphur atom;
Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced or polysubstituted by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, the peaceful base of phthalein (pthalaninyl), quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be substituted by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have the acyl group of the alkyl of 1-6 carbon atom, cycloalkyl or 1-7 carbon atom with 3-6 carbon atom, or R wherein 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R wherein 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R wherein 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Figure A9880301200631
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
(I) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R wherein 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(x) cyano group, or
(xi) amidino groups of following formula
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
R 2Be:
(A) hydrogen atom, or
(B) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom, wherein said alkyl or cycloalkyl can randomly be replaced by following groups:
(i) formula-OR 34Group, R wherein 34Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(ii) formula-NR 35R 36Group, R wherein 35And R 36Be hydrogen atom independently respectively, have the alkyl of 1-2 carbon atom or have the acyl group of 1-2 carbon atom;
R 3Be-(CR 37R 38) x(CR 39R 40) yR 41Group, wherein
X and y are respectively 0 or 1 independently,
R 37, R 38And R 39Be independently respectively:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
R 40Be:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(D) aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) R 43It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 44Group, R wherein 44Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 45R 46Group, R wherein 45And R 46Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 45And R 46Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 47R 48Group, R wherein 47And R 48Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 47And R 48Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 49Group, R wherein 49Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 50Group, R wherein 50Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(j) cyano group,
(k) nitro,
(l) amidino groups of following formula
R wherein 51, R 52And R 53Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 51, R 52And R 53In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(m) halogen,
(ii) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 43The single replacement,
(iii) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(iv) formula-COOR 54Group, R wherein 54Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(v) formula-NR 55R 56Group, R wherein 55And R 56Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 55And R 56Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 55And R 56In a group can be radicals R in addition 43,
(vi) formula-CONR 57R 58Group, R wherein 57And R 58Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 57And R 58Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 57And R 58In a group can be radicals R in addition 43,
(vii) formula-COR 59Group, R wherein 59Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 43,
(viii) formula-OR 60Group, R wherein 60Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 43,
(ix) formula-SR 61Group, R wherein 61Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 43,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently.
As mentioned above, some compounds of comprising of mentioned kind compound are known and have been disclosed in US3668217; US4944791; US3741981; Li, W.-Y; Deng the people, " pharmacology science magazine ", 1984,73,553-558 and Abd El Halim, M.S.; Deng people's " chemical monthly magazine ", 1994,125,1437-1442.
In a second aspect of the present invention, comprise novel cpd or its pharmacologically acceptable salt of formula I:
Figure A9880301200711
Wherein X, Y, Z, R 2, R 3, R 4, R 5And R 6Has above-mentioned identical implication, just R 3Aryl R in the part 41At least one hydrogen atom must be rather than randomly to be replaced by following groups:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
Figure A9880301200721
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen.
Preferably formula I novel cpd or its pharmacologically acceptable salt are, wherein:
Y is oxygen or sulphur atom;
Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
Figure A9880301200751
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Figure A9880301200762
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(the sulfonic acid group that v) has 1-6 carbon atom;
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
Figure A9880301200781
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently.
The novel cpd of preferred formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl, be selected from phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NH 2Group,
(g) formula-CONH 2Group,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(i) amidino groups of following formula
Figure A9880301200801
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(j) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(k) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(l) the quaternary group of following formula
Figure A9880301200811
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200812
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Figure A9880301200813
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazoles base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62It is aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be methyl,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be respectively hydrogen atom or methyl independently,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be respectively hydrogen atom or methyl independently,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or methyl,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be respectively hydrogen atom or methyl independently, and R wherein 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively hydrogen atom or methyl independently, and R wherein 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, methyl or R 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl;
R 5It is hydrogen atom; With
R 6Be Cl or trifluoromethyl.
The novel cpd of particularly preferred formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NH 2Group,
(g) formula-CONH 2Group,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(i) amidino groups of following formula
Figure A9880301200841
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(j) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(k) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(l) the quaternary group of following formula
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Figure A9880301200852
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom,
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl is selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyridazinyl and pyrazinyl,
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyridazinyl and pyrazinyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii) formula-COOR 63Group, R wherein 63Be methyl,
(iv) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl,
(v) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively methyl, and R wherein 76And R 77In a group be methyl, another group is R 62,
(F) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(G) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(H) cyano group,
(I) nitro, or
(J) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be Cl or trifluoromethyl.
The novel cpd of preferred especially formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl is selected from the group of phenyl or pyridyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(f) amidino groups of following formula
Figure A9880301200871
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(iii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
The (iv) quaternary group of following formula
Figure A9880301200872
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200881
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom,
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl is selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii) formula-COOR 63Group, R wherein 63Be methyl,
(iv) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(v) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted or can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by fluorine or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively methyl, and R wherein 76And R 77In a group be methyl, another group is R 62,
(F) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(G) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(K) cyano group,
(L) nitro, or
(M) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
The novel cpd of particularly preferred formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the alkyl of 1-2 carbon atom, described alkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl is selected from the group of phenyl or pyridyl
A hydrogen atom of wherein said aryl can randomly be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl, or
(f) amidino groups of following formula
Figure A9880301200901
R wherein 13, R 14And R 15Be respectively hydrogen atom, or
(iii) formula-OR 19Group, R wherein 19Be hydrogen atom or methyl,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200902
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom, or
(G) guanidine radicals of following formula
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom,
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be the group that is selected from phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) formula-COOR 63Group, R wherein 63Be methyl,
(iv) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(v) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted or can be by R 62The single replacement,
(C) formula-COOR 73Group, R wherein 73Be methyl,
(D) formula-COR 78Group, R wherein 78Be methyl or R 62,
(E) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(F) cyano group,
(G) nitro, or
(H) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
The novel cpd of preferred especially formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) methyl or ethyl, or
(C)-COCH 3
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be the group that is selected from phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) formula-COOR 63Group, R wherein 63Be methyl,
(iii) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(iv) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted or can be by R 62The single replacement,
(C) formula-COOR 73Group, R wherein 73Be methyl,
(D) formula-COR 78Group, R wherein 78Be methyl or R 62,
(E) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(F) cyano group,
(G) nitro, or
(H) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
The novel cpd of particularly preferred formula I or its pharmacologically acceptable salt be, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) methyl or ethyl, or
(C)-COCH 3
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) halogen,
(B) can be replaced by the fluorine atom list or polysubstituted methyl,
(C) formula-COR 78Group, R wherein 78Be methyl or R 62,
(D) halogen;
R 4It is the chlorine atom;
R 5It is hydrogen atom; With
R 6It is the chlorine atom.
The novel cpd of most preferred formula I is particular compound or its pharmacologically acceptable salt with following structural:
Figure A9880301200941
Synthesizing of compound of the present invention
Synthetic known in the prior art with those compound similar compounds of the present invention.According to its purpose, some approach can provide a spot of all cpds better, and other approach are more suitable in extensive synthetic concrete compound.Introduce several approach of synthetic these compounds below and by the corresponding approach embodiment of synthetic compound.
Need initial amino acid and its derivative of synthetic glycolylurea and sulfenyl-glycolylurea structure both can obtain from the market, also can improve one's methods and obtain (referring to for example: Williams, R.W. " desirable active alpha-amino acid whose synthetic " according to known references various; Pergamon:Oxford, 1989, " a-amino acid is synthetic "; O ' Donnell, M.J., Ed.; " announced tetrahedron collection of thesis "; Pergamon: London, 1988: the 44 volumes, the 17th edition, Jung, M.J. " chemistry of amino acids and biological chemistry "; Barrett, G.C., Ed.; Chapman and Hall: New York, 1985; The 227th page, and Spero, D.M.; Kapadia, S.R. " organic chemistry magazine ", 1996,61:7398-7401).Synthetic and the fractionation of 2-amino-2-(4-bromobenzyl)-ethyl propionate (initiator of embodiment 39) provides with embodiment.
At room temperature handle the 60 ml water solution 30 minutes of alanine ethyl ester hydrochloride (15.3 gram, 99.3 mmoles) with triethylamine (14.6 milliliters, 104.8 mmoles).Use twice in 100 milliliters of these mixtures of dichloromethane extraction then.Merge organic layer, use dried over sodium sulfate, vacuum concentration obtains the free alkali (productive rate: 86%) of 10.0 gram amino ester.Resistates is dissolved in the methylene dichloride once more, and in ice bath, cools off.Add sal epsom (11.3 grams, 93.9 mmoles), then add trimethyl-acetaldehyde (9.3 milliliters, 85.6 mmoles).Remove ice bath, stir the mixture and spend the night.Remove by filter sal epsom, vacuum concentrated filtrate obtains 11.8 gram imine intermediate (productive rates: 74.6%).
Above-mentioned imines (11.8 grams, 63.7 mmoles) is dissolved in the toluene (90 milliliters).Add 4-bromo benzyl bromo (17.5 grams, 70.1 mmoles), the cooling reactant is to-10 ℃ approximately.Add potassium tert.-butoxide (8.6 grams, 76.5 mmoles) with the speed that does not make temperature surpass 0 ℃.Reaction stirred is 2 hours in cooling bath, then with ether dilution and water (150 milliliters) washing.Dry organic layer (sodium sulfate) filters and vacuum concentration, obtains a kind of yellow transparent oil.Handle this oil and stir with 1NHCl (100 milliliters, 100 mmoles) and spend the night.With ethyl acetate (100 milliliters) extractive reaction thing, the water layer of 14.1 grams that obtain is racemic amino ester hydrochloride (productive rates: 68.7%).
This racemic compound is resolved to their component enantiomorph by various known technologies.Prepare 2-(R)-amino-2-(4-bromobenzyl)-ethyl propionate (initiator of embodiment 29) by racemize 2-amino-2-(4-bromobenzyl)-ethyl propionate by following method: restrain KH by 13.69 to 1.3 liters 2PO 4(Amano Enzyme USA limited-liability company, Lombardi IL), then add the hydrochloride of 12 gram racemic amino esters to add enzyme-lipase L10 that 20 grams obtain from the market in the damping fluid made from 2 premium on currency.Monitoring pH adds 1NKOH on demand, makes the pH of mixture remain on 6.4.Use the reversed-phase HPLC monitoring reaction course, after 2 days, the initiator of HPLC analysis revealed 50.4% is hydrolyzed.Add enough solid NaHCO this moment 3, to regulate pH to 8.1.Extract mixture twice with toluene, ether and EtOAc.The dry organic layer that merges concentrates and (EtOAC: purification crude product hexane) obtains 5.21 2-(R)-amino-2-(4-the bromobenzyl)-ethyl propionates that restrain (87%) with silica gel chromatography.Method A. makes initiator with amino acid and phenylcarbimide, uses sour cyclisation.
Suitable amino acid is dissolved in the aqueous solution of alkali (for example NaOH, KOH, Na 2CO 3, NaHCO 3, K 2CO 3Or KHCO 3) and be warmed to about 20-90 ℃.In mixture, add suitable isocyanic ester, stir the solution that forms and reach complete basically up to reaction.During cooling, acidifying mixture is by filtering or by extraction the Ureidoacetic acid that produces being separated in the organic solvent.Remove and desolvate, produce the intermediate Ureidoacetic acid.Press Sauli (US4099008) reported method, in the presence of the acid of catalytic amount (for example sulfuric acid, methylsulfonic acid, Phenylsulfonic acid or hydrochloric acid),, generate the glycolylurea that requires at organic solution or heated in water solution cyclisation intermediate Ureidoacetic acid.The glycolylurea that filters and purify and for example collect by silica gel chromatography or recrystallize processing.
Prepare the listed compound of table 1 with this general method.
Figure A9880301200961
Figure A9880301200971
Figure A9880301200981
Figure A9880301200991
Figure A9880301201001
Synthetic (referring to table 1) by embodiment 12 compounds be illustration method A exemplarily, described syntheticly carry out as follows.High phenylalanine (1.00 grams, 5.58 mmoles) is dissolved in the H of NaOH (0.28 gram, 6.69 mmoles) 2In the solution of O (10.0 milliliters) and 45 ℃ of heating down.When solution becomes when even, add 3,5-dichlorophenyl isocyanate (1.05 grams, 5.58 mmoles) is at 45 ℃ of following heated mixt more than 2 hours.Use then dense HCl acidifying through the refrigerative reaction mixture to pH=2-3.By filtering the collecting precipitation thing, wash with water, 50 ℃ of following vacuum-dryings, obtain 0.85 gram intermediate Ureidoacetic acid (thick productive rate: 42%).Then intermediate is dissolved in the solution of dense HCl (5.0 milliliters) and water (5.0 milliliters) reflux 5 hours.Make reaction mixture be cooled to room temperature, collect white solid, wash with water and, obtain 0.52 and restrain thick glycolylurea 50 ℃ of following vacuum-dryings by suction strainer.With EtOH recrystallize this material of purifying, obtain the compound of the embodiment 12 of 0.37 gram (45%).Method B. makes initiator with amino acid and phenylcarbimide, uses the EDC cyclisation.
Suitable amino acid is dissolved in the aqueous solution of alkali (for example NaOH, KOH, Na 2CO 3, NaHCO 3, K 2CO 3Or KHCO 3) and be warmed to about 20-90 ℃.In mixture, add suitable isocyanic ester, stir the solution that forms and reach complete basically up to reaction.During cooling, acidifying mixture is separated in the organic solvent by filtering or extract the Ureidoacetic acid that will produce.Remove and desolvate, produce the intermediate Ureidoacetic acid.In organic solvent (for example DMF, NMP or THF), adopt the dewatering agent (for example dicyclohexyl carbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC)) of any amount, ester activator (for example I-hydroxybenzotriazole hydrate (HOBT)) and non-nucleophilic base (for example triethylamine or N are being arranged, the N-diisopropylethylamine) exists down, the intermediate Ureidoacetic acid is cyclized into desired glycolylurea.They are used organic solvent extraction, then purify and for example handle by silica gel chromatography or recrystallize.
Prepare the listed compound of table 2 with this general method.
Figure A9880301201051
Figure A9880301201061
Figure A9880301201071
Synthetic (referring to table 2) by embodiment 15 compounds be illustration method B exemplarily, described synthesizing carries out as follows: to (R)-phenylalanine (0.33 gram, 2 mmoles) add 3 down at 50 ℃ in the 1 milliliter of 2NNaOH and the solution of 10 ml waters, 5-dichlorophenyl isocyanate (0.38 gram, 2 mmoles).The mixture of stirring generation is 1 hour then.Cooling solution is also handled up to forming throw out and making solution keep acid with dense HCl.Filter collecting precipitation thing and vacuum-drying, produce desired Ureidoacetic acid (0.60 gram, 85%).Ureidoacetic acid (0.35 gram, 1 mmole) is dissolved among 20 milliliters of DMF, at room temperature handled 1 hour with EDC (0.19 gram, 1 mmole) and HOBT (0.14 gram, 1 mmole).During this period, add N, N-diisopropylethylamine (0.35 milliliter, 2 mmoles) and stirring the mixture spends the night.With its water development, filtration is collected glycolylurea and is purified with silica gel chromatography.Productive rate in this embodiment is 0.20 gram (60%).Method C. makes initiator with amino ester or hydroxy ester and phenylcarbimide, with alkali or sour cyclisation.
With suitable amino ester or hydroxy ester and suitable isocyanic ester (for example NaOH, KOH, Na in the presence of alkali 2CO 3, NaHCO 3, K 2CO 3Or KHCO 3) be dissolved in the organic solvent (for example DMF, THF or DMSO) and be warmed between about room temperature to 60 ℃.After about 1 hour, make the temperature of reaction mixture rise to about 50-100 ℃, be complete up to reaction.Cooling solution then is with organic solvent (for example EtOAc or CH 2Cl 2) dilution.Then with the acid solution (for example 1N HCl) and the water washing organic phase of dilution, drying (is for example used MgSO 4) and concentrate.For example with silica gel chromatography or the required glycolylurea of recrystallize purification.(another kind of mode be a kind of acid for example the HCl aqueous solution in the presence of, be fully up to reaction by being heated to 50-100 ℃, and the Ureidoacetic acid ester be cyclized into glycolylurea).
Prepare the listed compound of table 3 with this general method.
Figure A9880301201111
Figure A9880301201121
Figure A9880301201131
Figure A9880301201141
Figure A9880301201151
The synthetic exemplarily illustration method C of embodiment 30 compounds by table 3, described syntheticly carry out as follows: at about 0.2 gram Na 2CO 3Existence under, with 2-amino-2-benzyl methyl-butyrate (0.21 gram, 1 mmole) and 3,5-dichlorophenyl isocyanate (0.19 gram, 1 mmole) is dissolved among the DMSO (5 milliliters), makes it 50 ℃ of stirrings 1 hour down.During this period, heated solution to 90 ℃ reaches 2 hours.Cooling solution with the EtOAc dilution, is used 0.1N HCl and water washing then.With dried over mgso organic layer and the concentrated crude product that produces, further purify with silica gel chromatography, obtain the compound of the embodiment 30 of 0.12 gram (33%).Method D. solid phase synthesis.
Disclose several embodiment in the document and prove that the synthetic of glycolylurea and its precursor amino acid derivative can carry out in solid phase, described solid phase can make various the synthesizing of these compounds be suitable for carrying out the automatization processing.In following documents and materials, provided the embodiment of synthetic precursor amino acid derivative: " Journal of the American Chemical Society ", 1996,118,6070-1, Tetrahedron Letters, 1997,38,7163-7188, Tetrahedron Letters, 1997,38,8821.Prove that the documents and materials that these amino acid derivative are converted into glycolylurea are " organic chemistry magazines ", 1997,62,6060-2.
By its carboxylic acid through suitable connexon; (Wang resin for example: 4-benzyloxy-benzyl polystyrene) amino acid that is connected on the solid-phase resin is protected on its nitrogen by means of reagent, and described reagent can make alpha-carbon alkylation (for example forming the benzaldehyde derivative of imines with amino acid whose nitrogen).Handle the protection compound with alkali and alkylating agent then, produce new protection amino acid derivative.The employing standard conditions are removed blocking group (under the situation of imines, for example implementing with the HCl aqueous solution) and are made free amine group and isocyanate reaction, produce intermediate urea.With this intermediate of agent treated, to the carboxylicesters end group of molecule, described molecule forms desired glycolylurea and decomposite product from resin with the cyclisation of catalyzing urea part.Purify by silica gel chromatography, reversed-phase HPLC recrystallize.
Prepare compound listed in the table 4 by this general method.
Figure A9880301201171
Figure A9880301201211
Figure A9880301201221
Figure A9880301201241
Figure A9880301201251
Figure A9880301201271
Synthetic exemplarily illustration method D by embodiment 67 compounds, described synthetic carry out as follows: commercially available Fmoc-Ala-Wang (300 milligrams, 0.150 mmole) and 3 milliliters are dissolved in 20% piperidine solution of N-Methyl pyrrolidone (pyrollidinone) in (NMP) pack in the reaction vessel.At room temperature, stirring reaction container 45 minutes on the track wobbler.Filter resin and wash (3 * 1 milliliters) with NMP.The reaction vessel that resin is housed is equipped with rubber septum, and is placed under the argon gas, packs 3 into, 4-dichlorobenzaldehyde (394 milligrams, 2.25 mmoles), trimethyl orthoformate (3.5 milliliters) and NMP (1.5 milliliters).The mixture that stirring at room temperature produces 15 hours.Filter to isolate solid resin, use NMP (3 * 3 milliliters), tetrahydrofuran (THF) (3 * 3 milliliters) and CH in succession 2Cl 2(3 * 3 milliliters) washing.About 1 hour of vacuum-drying resin produces the imide resin intermediate.
By with 2-tert-butyl imino--2-diethylamino-1,3-dimethyl perhydro--carotene 1,3,2-diaza phosphorine (BEMP, 0.217 milliliter, 0.75 mmole) and two kinds of reagent mix of NMP (3.5 milliliters), and this mixture at room temperature stirred on the track wobbler 15 hours, with 2,3-two fluoro-4-trifluoromethyl benzyl bromine (123.8 milligrams, 0.45 mmole) alkylation imide resin intermediates.The filtering separation solid is used NMP (3 * 3 milliliters), THF (3 * 3 milliliters) and CH in succession 2Cl 2(3 * 3 milliliters) washing, drying obtains alkylation imide resin intermediate.
Handle above-mentioned intermediate with the 1N HCl aqueous solution (1.8 milliliters) and THF (3.6 milliliters), at room temperature stirred 15 hours, isolate imines from above-mentioned intermediate.Isolate resin after filtration, and use NMP (3 * 3 milliliters), THF (3 * 3 milliliters) and CH in succession in conjunction with amino ester 2Cl 2(3 * 3 milliliters) wash and carry out vacuum-drying.
The step of final product is isolated in employing from resin, make the resin in conjunction with amino ester change into glycolylurea.The intermediate amino ester is packed in the reaction vessel, and with 3 milliliter of 20% N that is dissolved among the NMP, N-diisopropylethylamine solution is handled.At room temperature in argon gas, stir after 1 hour, filter resin,, and place vacuum with NMP (3 * 3 milliliters) and methyl alcohol (3 * 3 milliliters) washing.Subsequently, open container in argon gas, the 2.5 milliliters of 1.75M that pack into are dissolved in 3 of dimethyl formamide (DMF, 0.45 mmole), 5-dichlorophenyl isocyanate solution.With mixture at room temperature, under argon atmospher, stir and spend the night, from resin, isolate product by filtering.After with ethyl acetate (6 * 2 milliliters) washing resin, the organic solution that dilute with water merges, dried over sodium sulfate is used in the water (3 * 3 milliliters) and the saturated NaCl aqueous solution (2 * 3 milliliters) washing then, filters, and concentrates under nitrogen gas stream.Adopt reversed-phase HPLC (acetonitrile-water gradient) to carry out last purification.Method E. uses isocyanic ester and aniline as initiator.Carry out cyclisation with alkali or acid.
In the suitable isocyanic ester that is dissolved in (for example methylene dichloride) in the organic solvent, add suitable aniline, under about room temperature, in inert atmosphere, for example stirred the mixture 1-24 hour in the argon.In vacuum, remove organic solvent then.Remove excessive aniline (, or removing), isolate solid-state Ureidoacetic acid ester by the hurried chromatography of silica gel for example by boiling the rough solid in the hexane and decant liquid.With alkali (for example NaH, NaHMDS, Na 2CO 3, NaHCO 3, K 2CO 3Or KHCO 3) (for example THF or DMF) processing Ureidoacetic acid ester in organic solvent, then be warming to about 60-90 ℃, and it is cyclized into required glycolylurea.Then cooling solution dilutes with organic solvent (for example EtOAc).With the aqueous acid (for example 1N HCl) of dilution, wash with water then in succession, drying (is for example used MgSO 4) and concentrate.Press the required glycolylurea of silica gel chromatography or recrystallize method purification.(another kind of method is described by method C, acid for example the HCl aqueous solution in the presence of, by heating intermediate Ureidoacetic acid ester to about 90 ℃, and be cyclized into glycolylurea).
Prepare compound listed in the table 5 by this method. By the synthetic exemplarily illustration method E of embodiment 70 compounds, described synthesizing carries out as follows: be dissolved in anhydrous CH 2CH 2Add 3,4 in the solution of the 2-isocyanide acyl in (5.0 milliliters)-3-phenylpropionic acid ethyl ester (99.0 milliliters, 0.110 gram, 0.501 mmole), 5-trichloroaniline solid (0.1952 gram, 0.994 mmole).At room temperature, in argon atmospher, stirred the mixture 20 hours.This solution of vacuum concentration with this resistates twice of ethyl acetate/hexane recrystallize, obtains the white solid of the pure intermediate urea of 0.14 gram (65%) then.In anhydrous THF (4.0 milliliters), use the above-mentioned urea (0.108 gram, 0.260 mmole) that is dissolved in anhydrous (4.0 milliliters) to handle the suspension (dispersion in 0.06 gram, 60% mineral oil, 1.52 mmoles) of sodium hydride.At room temperature, in argon atmospher, stirred the mixture 1 hour.Then mixture is poured in 100 milliliters of 1N HCl aqueous solution.THF, filtering mixt are removed in decompression.By preparation thin-layer chromatography (SiO 2, 1: 1 hexane/ethyl acetate) and the described solid of purifying, obtain a kind of white solid, further purify with anhydrous EtOH recrystallize, obtain 0.027 gram pure compound (28%).Synthesizing of method F. succinimide
In the presence of the alkali (for example triethylamine) of catalytic amount, with suitable initial two acid or anhydrides of equimolar amount and suitable initial aniline in solvent (for example dimethylbenzene) backflow 2-24 hour.Solvent removed in vacuo, and residue is dissolved in (for example EtOAc) in a kind of organic solvent is in succession with the alkali aqueous solution of dilution (NaHCO for example 3) and aqueous acid (for example HCl) washing of dilution, dryly (for example use MgSO 4) and concentrate.For example purify by recrystallize or silica gel chromatography.
Initial diacid and acid anhydride both can be commercially available, also can prepare by the known references method.As embodiment, provided the synthetic of 2-benzyl-3-carboxyl-2-Methyl Butyric Acid (initiator of embodiment 74).
2.0 gram 2-methyl-3-phenylpropionic acids (12.2 mmole), the 2.2 gram carbonyl-diimidazoles (CDI, 13.56 mmoles) that will be dissolved in 20 milliliters of THF refluxed 1 hour under nitrogen atmosphere.Reduce temperature to 50 ℃, add 1.2 milliliters of crotyl alcohols (14.1 mmole), then add 20 milligrams of 4-(N, N-dimethylamino)-pyridine (DMAP).50 ℃ of following heated mixt 3 hours,, concentrate and purify with silica gel chromatography, obtain 1.7 gram intermediate ester: anti--crotyl-2-benzyl-3-carboxyl-2-Methyl Butyric Acid ester (64%).
Make described ester carry out [3,3] sigmatropic rearrangement, produce another kind of intermediate.In argon gas, under-78 ℃, (LDA, 3.25 mmoles are under-10 ℃, in 15 minutes, by 1.3 milliliters of positive BuLi of 2.5M and 0.54 milliliter of iPr of being dissolved among 3 milliliters of THF to the di-isopropyl acyl ammonia lithium that contains 500 microlitre DMPU 2The solution generation of NH) adds 560 milligrams of intermediate ester (2.57 mmole) solution that is dissolved among the THF (1 milliliter) in the THF solution.Stir this mixture 30 minutes, and added 480 milligrams of TBSCl (3.1 mmole) solution that is dissolved among 1 milliliter of THF subsequently.Under-78 ℃, stirred the mixture 30 minutes, at room temperature stirred 20 minutes, heated 10 hours down at 60 ℃ then.Cooling mixture to 0 ℃ is with 2N HCl (5 milliliters) quenching and at room temperature stirred 10 hours.Regulate the alkalescence of mixture with 2N NaOH, with ether (5 milliliters) extraction to pH10.Separate water layer, be acidified to pH1,, obtain the intermediate of 500 milligrams (89%): 2-benzyl-2,3-dimethyl-4-pentenoic acid with EtOAc extraction and concentrated with dense HCl.
By with the terminal alkene of ozone oxidation, single acid is changed into required diacid, with the intermediate of the further oxidation generation of chromium reagent.Under-78 ℃, 500 milligrams of 2-benzyls-2 in being dissolved in MeOH (20 milliliters), 3-dimethyl-4-pentenoic acid (2.29 mmole) and contain the O that feeds q.s in methylene dichloride (10 milliliters) solution of 120 microlitre pyridines rapidly 3Air-flow, it is light blue that solution is become.With 1 milliliter of methyl-sulfide treating mixture, and under-78 ℃, stirred 5 minutes.Warm then mixture concentrates to room temperature, makes it pass through silicagel column (with the CH of 10%MeOH 2Cl 2Solution is as eluting solvent) and concentrate.Rough material dissolution in 5 milliliters acetone, is at room temperature used Jones reagent (16 gram CrO 3, 16 the gram dense H 2SO 4100 ml water solution) handle up to being persistent orange.After adding entry (10 milliliters), stirred the mixture 1 hour, with EtOAc washing and concentrated.Make the silica gel chromatography purifying mixture of elutriant with 3%AcOH-EtOAc, obtain 300 milligrams of required diacid (55%).
Prepare the listed compound of table 6 by this method.
Figure A9880301201331
Figure A9880301201351
Synthetic (referring to table 6) by embodiment 72 and 73 compounds be illustration method F exemplarily, described synthesizing carries out as follows: initial diacid isomer (0.58 gram that will be dissolved in the embodiment 72 in the dimethylbenzene (5 milliliters), 1.8 mmole, 3: 1 mixtures of isomer), 3,5-dichlorphenamide bulk powder (0.35 gram, 2.2 mmoles), Et 3The mixture of N (10 milliliters, 0.07 mmole) refluxed 24 hours in the flask of being furnished with the Dean-Stark trap under argon gas.Cooling mixture, concentrate and purify (earlier with the hexane of 10% ethyl acetate with silica gel chromatography, the hexane of using 15% ethyl acetate again is as elutriant), (embodiment 73 to obtain 0.45 gram (52%) coelonychia base isomer, fusing point 139-140 ℃) and 15 milligrams (2%) suitable-methyl isomer (embodiment 72, fusing point=oil).Method G. carbonyl is converted into sulfenyl-carbonyl
Several reagent that carbonyl changed into sulfenyl-carbonyl are disclosed in the document.Typical step comprises that the matrix that will contain reagent is for example at the high boiling solvent P in the 1,2,3,4-tetralin for example 2S 3Heated 1-48 hour.Isolate product by the related standards condition, for example for example among the EtOAc, wash mixture diluted with water mixture to organic solvent, then with saturated NaCl solution washing, dry then and concentrated.Purify by silica gel chromatography or recrystallize, obtain required product.
Prepare the listed compound of table 7 with this general method. By the synthetic exemplarily illustration method G of embodiment 78 compounds, described synthesizing carries out as follows: initiator (1.5 grams, 3.5 mmoles) is dissolved in 5 milliliters of 1,2,3,4-tetralins, uses P 2S 3Handle (0.9 gram, 5.7 mmoles), be heated to 225 ℃ 2 hours.During cooling, the dilute with water mixture is extracted into product among the EtOAc.With saturated NaCl solution washing organic layer, dry and concentrated.With the residual oil of hexane development, obtain isolating after filtration yellow solid.(1: 4 EtOAc: this material of further purifying hexane) obtains the required compound of 1.13 grams (70%) by hurried chromatogram.Method H. sulfenyl-carbonyl is converted into the selective hydrolysis of carbonyl
Can with the compound selective that contains disulfide group-carbonyl that obtains by method G be hydrolyzed in two kinds of single sulfenyl-carbonyl compound each, this depends on selected condition.Usually more responsive at the locational sulfenyl-carbonyl of 4-of ring to the nucleophilic condition.Shown in embodiment 81,, then can make them change into 4-oxygen-class material with acid hydrolysis by using ethanolamine treatment.The locational sulfenyl-carbonyl of 2-at ring is nucleophilic more on sulphur, available methyl-sulfide alkylation.Use weak acid hydrolysis intermediate then.Obtain the compound of embodiment 80.Be easy to carry out the purification of this compounds by silica gel chromatography or recrystallize.
Prepare the listed compound of table 8 with this general method.
Figure A9880301201391
Handle with 10 milliliter of 50% thanomin aqueous solution and to be dissolved in 3 milliliters of initiator (0.23 gram, 0.49 mmole) solution among the THF, and reflux 2 hours and preparation embodiment 80.During cooling, extract described mixture with EtOAc, water and saturated NaCl solution washing organic layer, drying obtains a kind of brown solid with concentrating.Handle this solid with 20 milliliters of 6NHCl then, reflux 72 hours.During cooling, extract mixture with EtOAc, with saturated NaCl solution washing organic layer, dry and concentrated.With preparation type TLC silica gel purified product, with 1: 1 EtOAc: hexane is as solvent, obtains productive rate and be 34% product.
In 1.6 milliliters of 2NNaOH, handle initiator (0.5 gram, 1.09 mmoles) solution and prepare embodiment 81.When compound begins not dissolve, add 1 ml water and 1 milliliter of THF with hydrotropy.Cooling mixture in ice bath dripped Me in 5 minutes then 2SO 4(0.12 milliliter, 1.3 mmoles).In 0 ℃ of following restir mixture 3 hours, at room temperature stirred then 45 minutes.This reactant of 1NHCl quenching that adds q.s is so that the pH of solution is lower than 2.Extract mixture with EtOAc, dry and concentrated with saturated NaCl solution washing organic layer, obtain a kind of yellow oil body.Handled this oil body and reflux 3 hours with 10 milliliters of 6NHCl then.During cooling, extract described mixture with EtOAc, with saturated NaCl solution washing organic layer, dry and concentrated.Use the silica gel column chromatography purified product, with 1: 1 EtOAc: hexane was as solvent, obtained productive rate and be 5% product.The N-alkylation of method I. glycolylurea
Suitable glycolylurea is dissolved in (for example DMF, THF or DMSO) in a kind of aprotonic solvent, and (for example NaH, LDA, LiHMDS, KH or NaHMDS) handles with 1 normal alkali.After about 10 minutes to 1 hour, add suitable alkylating agent, stirring the mixture under about room temperature to 90 ℃ reaches 24 hours.(available TLC monitoring reaction course).Cooling solution then is with organic solvent (for example EtOAc or CH 2Cl 2) dilution.Use diluted acid (for example 1NHCl) and water washing organic phase in succession, drying (is for example used MgSO 4) and concentrate.With silica gel chromatography or the required glycolylurea of recrystallize purification.
Prepare the listed compound of table 9 by this general method.
Figure A9880301201411
Figure A9880301201441
Figure A9880301201451
Figure A9880301201461
Figure A9880301201481
Figure A9880301201491
Figure A9880301201501
Figure A9880301201511
Figure A9880301201521
Figure A9880301201531
Figure A9880301201561
Figure A9880301201571
Figure A9880301201581
Figure A9880301201591
Figure A9880301201601
Figure A9880301201611
Figure A9880301201621
Figure A9880301201631
Figure A9880301201641
Figure A9880301201651
Figure A9880301201661
Figure A9880301201671
Figure A9880301201681
Synthetic exemplarily illustration method I by embodiment 97 (referring to table 9) compound, described synthesizing carries out as follows: with initiator (0.21 gram, 0.5 mmole) be dissolved among the DMF (5 milliliters), use (0.5 milliliter of 1M NaHMDS in succession, 0.5 mmole) and this solution of solution-treated of EtI (0.04 milliliter, 0.5 mmole).After 1 hour, this reaction mixture is assigned in EtOAc and the water, washes organic phase with water, use MgSO 4Dry.Carry out silica gel column chromatography, obtain the required product of 0.17 gram (72%).Method J. heterocyclic C-alkylation
Suitable heterocycle is dissolved in (for example DMF, THF or DMSO) in the aprotonic solvent, approximately-78 ℃ to the room temperature with 1 normal alkali (Et for example 3N, LDA, KHMDS, LiHMDS or NaHMDS) handle.After about 10 minutes to 2 hours, add suitable alkylating agent, stirring the mixture under about 0-90 ℃ reaches 24 hours.(available TLC monitoring reaction course).Cooling solution dilutes with organic solvent (for example EtOAc) then.Use diluted acid (for example 1NHCl) and water washing organic phase in succession, drying (is for example used MgSO 4) and concentrate.As the required glycolylurea of purifying with silica gel chromatography or recrystallize.
Prepare the listed compound of table 10 by this general method.
Figure A9880301201711
Figure A9880301201721
Figure A9880301201731
Figure A9880301201751
Figure A9880301201761
Figure A9880301201781
Figure A9880301201811
Figure A9880301201831
Figure A9880301201841
Figure A9880301201851
Figure A9880301201871
Synthetic exemplarily illustration method J by embodiment 148 (referring to table 10) compound, described synthesizing carries out as follows: initiator (0.11 gram, 0.40 mmole) is dissolved in (-78 ℃ approximately) cooling among the THF (5.0 milliliters) and in dry ice/acetone batch.Drip two (trimethyl silyl) lithium amides (LiHMDS, 405.0 microlitres, 0.40 mmole).The yellow solution that stirring produces in cooling bath 15 minutes, this moment is to wherein adding the 2-fluoro benzyl bromide.Under this temperature, stirred the mixture 30 minutes again, stirred 30 minutes down at 0 ℃ then.Then reaction mixture is poured among the 1NHCl (40 milliliters), and collection is gone among the EtOAc (50 milliliters).With the saturated NaCl aqueous solution (35 milliliters) washing organic layer, dry (Na 2SO 4), filter and vacuum concentration, obtain 0.16 gram crude product.(1: this material of the purifying 3EtOAc/ hexane) obtains the compound of the embodiment 148 of 0.87 gram (57.0%) by the hurried chromatogram of silica gel.Method K. methyl carbonic acid magnesium C-alkylation glycolylurea
According to the report of Finkbeiner (" organic chemistry magazine ", 1965,30,3414), available methyl carbonic acid magnesium (MMC) is with alkylogen C-alkylation glycolylurea.Under about 80 ℃, during about 1 hour in, use CO 2The saturated MMC solution that is dissolved in the organic solvent (for example DMF).Add then suitable glycolylurea and and MMC heated the alkylogen that this moment, adding suited together about 1-2 hour.Warm reaction mixture is cooled to about room temperature then to about 110 ℃ in about 2-3 hour time.Then mixture is poured in the concentrated acid aqueous solution (for example HCl) on ice and cooling.Filter and collect the solid that forms, purify, obtain required product with silica gel chromatography and/or by recrystallize.
Prepare the listed compound of table 11 by this method.
Figure A9880301201891
By the synthetic exemplarily illustration method K of embodiment 181 compounds (referring to table 11), described synthesizing carries out as follows: the two neck round-bottomed flasks that will do vacuumize and charge into CO 2Gas.In flask, add and be dissolved in DMF (860 microlitres, 2.0M) the methyl carbonic acid magnesium in, heated solution to 80 ℃.Import CO by the sleeve pipe that is connected with reaction vessel from the dry ice container 2, in solution, blasted bubble 1 hour, connect tunger tube this moment and remove Decanning.Add the initiator (0.21 gram, 0.86 mmole) be dissolved among the DMF (4.0 milliliters), in 80 ℃ of following reacting by heating mixtures 1.5 hours.Drip the solution of the 3-pyrmethyl chloride (0.12 gram, 0.94 mmole-HCl salt are earlier with the free alkalization of NaOH) that is dissolved among the DMF (1.0 milliliters) then.Make the temperature of oil bath be elevated to 110 ℃, heated mixt is 4.0 hours under this temperature.During cool to room temperature, mixture is poured in the mixture of 5 milliliters of concentrated hydrochloric acids and 10 gram ice, leave in the refrigerator then and spend the night.Then use the 6NNaOH neutralization solution to pH7-8, suction strainer is collected the solid that produces, and washs with frozen water.Dry this compound under 50 ℃ vacuum obtains 0.20 gram crude product.By hurried chromatogram (5%MeOH/CH 2Cl 2) purify, obtain 0.06 gram material, by further purifying, obtain the compound of the embodiment 181 of 0.04 gram (14.9%) with the EtOH recrystallize.Method L. adopts the catalytic crosslinked coupling synthetic compound of Pd
The aryl boric acid (arylboronic acid) of suitably replacement or the tetrakis triphenylphosphine palladium of aryl stannane and aryl halide or aryl triflate and catalytic amount (are for example contained alcoholic acid benzene and Na in the appropriate solvent system 2CO 3The aqueous solution, DMF, NMP or THF) under inert atmosphere, mix.Can add other compound on demand, for example LiCl and triethylamine.At 50-150 ℃ of following heated mixt 2-48 hour.Then cooling mixture dilutes with organic solvent (for example EtOAc).Water and saturated NaCl solution washing organic phase are dry (as using Na successively 2SO 4) and concentrate, obtain impure material, adopt silica gel chromatography to separate and obtain desired substance.
Prepare compound listed in the table 12 by this method.
Figure A9880301201921
Figure A9880301201941
Figure A9880301201961
Figure A9880301201971
Figure A9880301201981
Figure A9880301201991
Figure A9880301202001
Figure A9880301202011
Figure A9880301202031
Figure A9880301202041
Figure A9880301202051
By the synthetic exemplarily illustration method L of embodiment 182 compounds (referring to table 12), described synthesizing carries out as follows: according to Miyaura, and M; Yanagi, T; Suzuki, A.Synth.Commun.1981, II, 513 described method, with initiator (0.24 gram, 0.54 mmole) and phenyl-boron dihydroxide (0.73 gram, 0.60 mmole), tetrakis triphenylphosphine palladium (0) (0.31 gram, 0.03 mmole), yellow soda ash (0.19 gram, 1.79 mmoles), benzene (3.0 milliliters), water (1.0 milliliters) and ethanol (1.0 milliliters) mixing and stirring and refluxing are 12 hours.Then reaction mixture is poured among the EtOAc (70 milliliters), successively water and saturated NaCl solution washing.Dry (Na 2SO 4) organic layer, filter and vacuum concentration, obtain 0.25 gram crude product.(1: 3, then 1: this material of the purifying 1EtOAc/ hexane) obtained the compound of the embodiment 182 of 0.11 gram (48%) with twice continuous silica gel chromatographic column.Method M. adopts the Pd catalytic crosslinking coupling synthetic compound of carbonylation
The aryl boric acid (arylboronic acid) of suitably replacement or the tetrakis triphenylphosphine palladium of aryl stannane and aryl halide or aryl triflate and catalytic amount (are for example contained alcoholic acid benzene and Na in the appropriate solvent system 2CO 3The aqueous solution, DMF, NMP or THF) under carbon monoxide atmosphere, mix.Can add other compound on demand, for example LiCl and triethylamine.At 50-150 ℃ of following heated mixt 2-48 hour.Then cooling mixture dilutes with organic solvent (for example EtOAc).Water and saturated NaCl solution washing organic phase are dry (as using Na successively 2SO 4) and concentrate, obtain impure material, adopt silica gel chromatography to separate and obtain desired substance.
Prepare compound listed in the table 13 by this method.
Figure A9880301202091
Synthetic exemplarily illustration method M by embodiment 215 compounds (referring to table 13), described synthesizing carries out as follows: with initiator (0.23 gram, 0.53 mmole) with (0.86 milliliter of phenyl tributyl stannane, 2.64 bi triphenyl phosphine-Palladous chloride (II) (0.037 gram mmole),, 0.05 mmole), DMF (10.0 milliliters) and LiCl (5.1 milligrams, 1.6 mmoles) mix usefulness argon gas purge reaction mixture, charge into CO, stirred 12 hours down at 115 ℃.Then reaction mixture is poured in the 1M tetrabutylammonium (10 milliliters), with 95 milliliters of EtOAc dilutions, water and saturated NaCl solution washings successively.Dry (Na 2SO 4) organic layer, filter and vacuum concentration, obtain 1.2 gram crude products.By silica gel chromatography (1: 3 EtOAc/ hexane) this material of purifying, obtain the compound of the embodiment 215 of 0.14 gram (48%).Method N. electrophilic aryl replaces
Replace by the electrophilic aryl, change the compound that contains aryl rings with all ingredients.They comprise carries out acidylate, nitrated, sulfonation and halogenated technology to these rings.
Prepare compound listed in the table 14 by this method.
Figure A9880301202111
The compound of embodiment 217 is such a case and by the preparation of following method.Use NaIO 3(0.05 gram, 0.2 mmole) and I 2(0.06 gram, 0.5 mmole) handled and is dissolved in 1 milliliter of HOAc and 0.1 milliliter of H 2SO 4In initiator (0.4 gram, 1.1 mmoles) solution.Heated mixt to 70 ℃ reaches 19 hours then, after this, it is cooled to room temperature, with the EtOAc extraction several times.Concentrate EtOAc, after purifying, isolate product with silica gel chromatography.Productive rate: 33 milligrams (30%).Method O. removes with the blocking group in the compound of acid-unstable group protection
Can be by currently known methods by under acidic conditions, handling the blocking group that can remove with in the compound of acid-unstable group protection.Be usually included in heating or not under the heating condition, in AcOH, handle this material with TFA, Zeo-karb (H+), HCl or HBr.Collect the compound that forms thus by filtering or extracting, and purify, obtain required product by silica gel chromatography or recrystallize method.
Prepare compound listed in the table 15 by this general method.
Figure A9880301202131
Figure A9880301202151
Figure A9880301202171
Figure A9880301202181
Synthetic exemplarily illustration method O by embodiment 219 compounds, described synthesizing carries out as follows: will be dissolved in 10 milliliters of initiators (0.10 grams in the methylene dichloride, 0.19 stirred solution mmole) is cooled to 0 ℃, adds 2.0 milliliters of trifluoroacetic acids then.0 ℃ of following continuously stirring 20 minutes, make solution slowly be warmed to room temperature then.Restir solution 6 hours concentrates at the moment, obtains a kind of pure white solid, further dry in a vacuum 16 hours.Then, make mixture be cooled to room temperature with 10 milliliters of these rough solids of ebullient hexane development.Filter and collect the white precipitate that produces, with 5 milliliters of hexane wash, drying is 4 hours under high vacuum, obtains 0.06 gram (productive rate: the compound of embodiment 219 68%).Method P. forms acid with oxyhydroxide saponification ester
Can be by currently known methods, have some compound of carboxylicesters with the saponification agent treated, make it be transformed into carboxylic acid.This method generally comprises with being dissolved in for example H of solvent 2NaOH among the O, KOH or LiOH (containing for example THF of solubilizing agent sometimes) handle this material.Purification generally includes with a kind of organic solvent for example EtOAc or CH 2Cl 2Extract unreacted initiator, acidifying water layer and by filtering or collection is gone into organic solvent for example EtOAc or CH 2Cl 2And purify.Further purification can adopt recrystallize, silica gel chromatography or reversed-phase HPLC to carry out, and obtains required product.
Prepare compound listed in the table 16 by this general method.
Figure A9880301202241
Prepare embodiment 239 (table 16) by following method: by initiator (0.38 gram, 0.65 mmole) is dissolved in 4 milliliters of H 2O and 8 milliliters contained among the MeOH of LiOH (0.08 gram, 1.95 mmoles), 60 ℃ of heated mixt 2.5 hours.Concentrate and remove MeOH, handle the remaining aqueous solution with 1NHCl.Use the EtOAc extraction product, during cooling carry out crystallization.Productive rate: 262 milligrams (72%).Method Q. division phthalic imidine (Pthalimide) blocking group
Primary amine can be used as its phthalimide derivative and protects.Adopt the sylvite of phthalic imidine to synthesize these derivatives rapidly as nucleophilic reagent by method U.Available nucleophilic reagent for example be dissolved in solvent for example hydrazine or the methylamine among the EtOH from the phthalic imidine blocking group, discharge amine.Purification generally comprises the acidifying water layer and with organic solvent for example EtOAc or CH 2Cl 2Extract unreacted initiator.The alkalization water layer produces the free alkali of amine, filters, or with organic solvent for example EtOAc or CH 2Cl 2The extraction and purify.Further purification can adopt recrystallize, silica gel chromatography or reversed-phase HPLC to carry out, and obtains required product.
Prepare compound listed in the table 17 by this general method. The compound for preparing embodiment 240 by following method: initiator (by method U preparation, 0.72 gram, 1.2 mmoles) is dissolved among 73 milliliters of EtOH, with 19.5 milliliter of 33% MeNH that is dissolved among the EtOH 2Solution is handled.This mixture of reflux 2.5 hours is cooled to room temperature then.Concentrated reaction mixture, and residue is dissolved in CH 2Cl 2In, further use H 2O and saturated NaCl solution washing.Dry (Na 2SO 4) organic layer and concentrated.Yellow oil is dissolved among the EaOH, uses the HCl gas disposal.Obtain the compound amine hydrochlorate of embodiment 240, productive rate: 69% (0.49 gram).Method R. is converted into into amidine with nitrile
Can fragrant nitrile be converted into amidino groups by several method.This conversion is generally carried out in two steps, and wherein the first step comprises with acid (for example HCl) and pure (for example MeOH or EtOH) and handling, and produces a kind of intermediate imido ether.By handling this derivative is changed into amidine then with amine.Generally the mode of the derivative salt by the recrystallize amidine is purified.Further purification can adopt recrystallize, silica gel chromatography or reversed-phase HPLC to carry out, and obtains required product.
Prepare compound listed in the table 18 by this general method.
Figure A9880301202281
The compound of embodiment 243 is by the preparation of following method: initiator (0.2 gram, 0.4 mmole) is dissolved among 7 milliliters of EtOH, and cooling mixture in ice bath was with anhydrous HCl gas processing mixture 15 minutes.At room temperature stir the mixture also concentrated in 1 hour, obtained rough imido ether hydrochloride.Intermediate is dissolved among the EtOH (10 milliliters) cooling and use anhydrous NH in ice bath 3Gas processing 20 minutes.After 5 hours, concentrated reaction mixture produces rough amidine hydrochloride.With silica gel chromatography (1: 9MeOH: CH 2Cl 2) this material of purifying, obtain 0.08 the gram (38%) product.Method S. is reduced into alcohol with carboxylic acid
Have some compound of carboxylic acid by currently known methods with the reduction agent treated, can make it change into alcohol.This method generally comprises uses LiAlH 4Or BH 3Base reagent is for example handled this material in THF or the ether in solvent.After with the careful quenching of a kind of aqueous systems, purify, generally comprise product is come together into organic solvent for example EtOAc or CH 2Cl 2In and adopt recrystallize, silica gel chromatography or reversed-phase HPLC to purify, obtain required product.
Prepare compound listed in the table 19 by this general method.
Figure A9880301202301
The compound for preparing embodiment 244 by following method: initiator (by method J and O preparation, 0.16 gram, 0.32 mmole) is dissolved among 1 milliliter of THF, and cooling mixture in ice bath is with 0.65 milliliter of 1M BH 3-THF solution (0.65 mmole) is handled.Make mixture be warming to room temperature, stirred 15 hours.Slowly and carefully add the described mixture of entry quenching, organic compound is come together into EtOAc.Water, saturated NaCl solution washing EtOAc layer are used Na 2SO 4Dry.Concentrate and silica gel chromatography (1: 1 EtOAc: the required compound of Chan Shenging (0.06 gram, 42%) hexane).Method T. nucleophilic reagent deprotection compound
Press currently known methods, but handle some compound and deprotection and become hydroxy derivatives with methoxyl group blocking group with some nucleophilic reagents.This method generally comprises with being dissolved in for example CH of solvent 2Cl 2In Bbr 3Or TMSI handles this material, cools off in ice bath usually, then heating or do not heat.After about 10 minutes to 8 hours, with weak base NaHCO for example 3The quenching reaction mixture comes together organic compound into solvent EtOAc for example, purifies concentrating the back, is for example undertaken by silica gel chromatography or recrystallize method, obtains required product.
Prepare compound listed in the table 20 by this general method.
Figure A9880301202321
Figure A9880301202331
By the synthetic exemplarily illustration method T of embodiment 246 compounds, described synthetic method is as follows: will be dissolved in 9 milliliters of CH 2Cl 2In the stirred solution of initiator (0.35 gram, 0.64 mmole) freezing to 0 ℃, add 1.0 milliliters of BBr then 3(1.07 mmoles, lM CH 2Cl 2).Continue to stir, make solution slowly be warming to room temperature then.Restir solution 4 hours adds saturated NaHCO at the moment 3The aqueous solution is removed organic layer and concentrated, obtains crude product.With silica gel chromatography (1: 4EtOAc: hexane) purify, obtain 0.16 gram (productive rate: required compound 48%).Method U. nucleophilic substitution
Suitable electrophilic reagent is dissolved in a kind of aprotonic solvent in (for example DMF, THF or DMSO), and with the normal nucleophilic reagent of 1-3 (Me for example 3The Na salt of N, imidazoles, Na 2SO 3, NaCN, P (OEt) 3Or the first salt of phthalic imidine) under the temperature of room temperature to 100 ℃, handle.Under about 0-100 ℃ temperature, stir the mixture to nearly 24 hours.(available TLC monitoring reaction course).Cooling solution dilutes with organic solvent (for example EtOAc) then.Use dilute acid solution (for example 1N HCl) and water washing organic phase in succession, drying (is for example used MgSO 4) and concentrate.The purification required compound is as being undertaken by silica gel chromatography, reversed-phase HPLC or recrystallize method.
Prepare compound listed in the table 21 by this general method.
Figure A9880301202351
Figure A9880301202361
Figure A9880301202371
Figure A9880301202391
Figure A9880301202411
Synthetic exemplarily illustration method U by embodiment 262 compounds, described synthetic method is as follows: add 1-H-pyrazoles carboxyl amidine (0.08 gram, 0.54 mmole) in initiator (0.28 gram, 0.54 mmole), then add 7 milliliters of DMF and 0.2 milliliter of N, N-two different phenyl-ethamine.The mixture of stirring generation at room temperature is 15 hours then.Then add ether, make mixture become muddiness.Do not having when crystal formation, adding MeOH, the solubilizing reaction component adds 1N HCl and makes product with its hydrochloride form precipitation once more.Collect solid and, obtain 0.11 gram (20%) guanidinesalt hydrochlorate with the ether washing.Method V. splits the mixture of enantiomorph
There is several method compound of the present invention can be split as the form of its enantiomer-pure.A kind of method is chirality HPLC.An exemplary column packed is Chiracel-OD (a Diacel chemical industry).An exemplary solvent system is 9: 1 hexanes: different-propyl alcohol.Usually wash-out R enantiomorph at first, but should be as determining stereochemical sole criterion.
Prepare compound listed in the table 22 by this method.
Figure A9880301202431
The description of biological nature
The biological nature of formula I representative compounds is studied by testing program described below.Hereinafter listed this class test-results in the table 23.Measure and suppress the test test objective of LFA-1 in conjunction with ICAM-1:
This testing program is to study CAM, ICAM-1 and the white interactional direct antagonism of integrin CD18/CD11a (LFA-1) by test compound.The description of testing program:
Employing is taken from 20 gram TS2/4 antibody of pills of human body JY or SKW3 cell and immune purifying LFA-1, existing in the prior art (Dustin, the M.J. of describing of the scheme that is adopted; Deng the people " IMMUNOLOGY KEY WORDS INDEX, 1992,148,2654-2660).By on TS2/4LFA-1mAb sepharose (Sepharose), carrying out immunoaffinity chromatography and the LFA-1 that from the SKW3 lysate, purifies, under pH11.5, at 2mM MgCl 2With carry out wash-out under the existence of 1% octyl glucoside., merge sample and use Protein G agarose preclearing behind the fraction from the TS2/4 post in collection and neutralization.
Press ICAM-1 (Marlin, the S. of description structure, expression, purification and the sign soluble form of prior art; Deng the people, " nature ", 1990,344,70-72 and, A. referring to Arruda; Deng the people, Antimicrob.Agents Chemother.1992,36,1186-1192).In brief, adopt the oligonucleotide directed mutagenesis of standard will be positioned at the structural domain 5 of extracellular domain and the Isoleucine 454 of inferring at the interface between the membrane spaning domain changes to terminator codon.This structure produced one with film in conjunction with the identical molecule of first 453 amino acid of ICAM-1.The coding region that makes up with hamster dihydrofolate reductase gene, Xin Meisu-resistance marker and above-mentioned sICAM-1 produces expression vector with the polyadenylation signal in promotor, splicing signal and the early stage field of SV40.The calcium phosphate method of employing standard with the plasmid recombinant transfection in the CHODUX cell.Cell is gone down to posterity in elective medium (G418), and adopts the bacterium colony of methotrexate amplification secretion sICAM-1.Adopt traditional non-affinity chromatography technology to comprise ion-exchange and the size exclusion chromatography sICAM-1 that from serum free medium, purifies.
At first the 40 mcg/ml sICAM-1s of incubation in the phosphate buffered saline (PBS) of the Dulbecco that contains calcium and magnesium then add 2mM MgCl in 96 orifice plates 2With 0.1mM PMSF (dilution buffer liquid), incubation 30 minutes combining at room temperature with monitoring LFA-1 and ICAM-1.Add 2% (w/v) then and be dissolved in bovine serum albumin in the dilution buffer liquid, at 37 ℃ of these plates of sealing 1 hour down.Remove confining liquid from the hole, the dilution test compound adds the LFA-1 of the affine purification of about 25 nanogram(ng)s immunity then.In the presence of test compound and ICAM-1, at 37 ℃ of incubation LFA-11 hours.Wash this hole 3 times with dilution buffer liquid.Add with CD18 kytoplasm afterbody (being diluted to 1: 100 extent of dilution) with dilution buffer liquid and 1% BSA corresponding at peptide polyclonal antibody and detect bonded LFA-1, and make it 37 ℃ of incubations 45 minutes.With rare damping fluid washing hole 3 times, add to be conjugated at 1: 4000 and monitor the bonded polyclonal antibody at the horseradish peroxidase on the goat immunoglobulin (Ig) of rabbit immunoglobulin.Make reagent 37 ℃ of following incubations 20 minutes, washing hole as stated above adds the substrate of horseradish peroxidase in each hole, with launch be attached to sICAM-1 on the LFA-1 amount be directly proportional quantitatively than chrominance signal.The ICAM-1 of solubility (60 mcg/ml) is as suppressing the interactional sun contrast of LFA-1/ICAM-1.Do not add contrasting of LFA-1 in conjunction with the background of test as all samples.Obtain the dosage-response curve of all test compounds.
Write down the result of these tests with μ M by Kd ' s.Measure Cytotoxic MTT test test objective:
In order to obtain significant test cell line data, must first measure the cytotoxicity of compound at first in test.The MTT test can be used for this purpose.The description of testing program:
MTT, (3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene-2H-tetrazolium bromide) is a kind of yellow substrate, they are had active mitochondrial lysis, to produce a kind of mazarine/purple first  product.This throw out can be dissolved and can be by amount (Gerlier, the D of spectrophotometry quantitative material; Thomasset, N. " immunization method magazine ", 1986,94,57-63).The amount of color is directly proportional with the quantity of survivaling cell.External, this pilot system is the influence that is used in vitro test test compound pair cell viability.
Use the SKW3 cell of expressing LFA-1.The cell that uses in each test is adjusted to 1.25 * 10 6Cells/ml also is distributed to this stock of 100 microlitres in each hole in 96 holes of flat-bottom microtiter plates.In concrete test,, set up three holes for every kind of condition.The serial dilution or the single carrier of each test compound are joined in each hole.Before the test viability, use compound incubation cell 4-24 hour down at 37 ℃.The MTT that then in each hole, adds the filtration sterilization of 10 microlitres.The MTT stock of prepared at concentrations in phosphate buffered saline (PBS) with 5 mg/ml.Then with this plate at 37 ℃, 5% CO 2Incubation is 1 hour under the atmosphere.The first crystalline of check-out console produces termly.
After incubation finished, the HCl that is dissolved in the isopropyl alcohol by adding 100 microlitre 0.04N in each hole dissolved the first crystal.Repeat to move liquid to mix each hole fully with multichannel pipettor.Plate was placed under the room temperature 15-20 minute, read by means of spectrophotometer then.Measure absorbancy in tested wavelength 570 nanometers.
The data of record concentration range (μ M), wherein 50% cell is no longer survived.Measure the test test objective that suppresses with ICAM-1 bonded SKW3 cell and fibronectin bonded:
This test is used for cell combining form and the interactional selective power of ICAM-1 of testing experiment compound antagonism LFA-1.Human body T clone, SKW3 cell are used in test, and they express the integrin that CD18, CD11a and other and CD18, CD11a have nothing to do and pass through Buddhist ripple ester " activation ".Buddhist ripple ester has strengthened the CD18 that is used for ICAM-1, the affinity of CD11a.
Identical lymphocyte series, SKW3 also adheres on the fibronectin in the presence of phorbol ester.Irrelevant membrane protein mediates by interacting with LFA-1/ICAM-1 in this adhesion.Another integrin of SKW3 cell expressing, VLA4, they are acceptors of fibronectin.Therefore, as test compound to the interaction of disturbing white integrin/CAM but do not have other integrin-cooperation in conjunction with the optionally tentatively indication under the situation, under the interactional situation of the fibronectin of compound and purifying, can test this compound to the ability of antagonism cell in conjunction with fibronectin receptor.The compound that suppresses this fibronectin adhesion is not CD18, CD11a/ICAM-1 bonded specific antagonist.The description of testing program:
The sICAM-1 (40 mcg/ml) or the fibronectin (100 mcg/ml) that at room temperature are used in the dilution buffer liquid applied 96 orifice plates 1 hour.Xiang Kongzhong add 100 microlitres suitably dilution test compound or in contrast 100 microlitres of thing contain the RPMI of 15% foetal calf serum.SKW3 cell (Dustin, the M. of CD18, CD11a and VLA4 expressed in washing; Deng people's " The Journal of Experimental Medicine ", 1987,165,672-692) and to be suspended to concentration in the RPMI with 15% foetal calf serum be 10 6Cells/well.Before joining cell in the hole, be Buddhist ripple ester 12-myristinate 13-acetic ester (PMA) irritation cell of 100 mcg/ml immediately with ultimate density.Add 100 microlitre cells then in the hole, making ultimate density is 50 mcg/ml PMA and 2 cells/well.This plate of 37 ℃ of following incubations 2 hours.Wash away not combination or loose bonded cell lentamente with RPMI.Identical reagent quantitative analysis cell that keeps and the amount that therefore is attached on ICAM-1 or the fibronectin with the above-mentioned MTT of being used for test.
With concentration or concentration range (pressing μ M) record data, wherein 50% combination has been subjected to inhibition.Compound suppresses JY cell aggregation test objective:
Carry out cell and cell adhesion test external, this test can be used for testing that test compound directly suppresses ability to the accumulative that depends on LFA-1 under cell concn.
Many Epstein-Barr virus cell transformed present gathering.Gathering can strengthen by adding Buddhist ripple ester.Find (Rothlein, R.R. that this class homotypic aggregation (promptly comprising the only gathering of a cellular type) can seal by anti-LFA-1 antibody; Deng people's " The Journal of Experimental Medicine ", 1986,163,1132-1149).Therefore, LFA-1 dependency bonded degree can be determined by measuring degree spontaneous or Buddhist ripple ester dependency aggregated forms.
A kind of interference LFA-1 dependency accumulative preparation can differentiate that this test can determine whether medicine disturbs the spontaneity of Epstein-Barr virus transformant to assemble or Buddhist ripple ester dependency is assembled by adopting a kind of test.Preferably use cell (Terhost, the L. of JY clone; Deng the people, Proc.Natl.Acad.Sci.USA, 1976,73,910) be used for the homotypic aggregation test.This LFA-1 dependency accumulative of measuring is tested, and can be used for differentiating the preparation of the LFA-1 dependency having been assembled antagonist action.This preparation can work by weakening LFA-1 or ICAM-1 mediation accumulative ability.Therefore, if LFA-1 accumulative antagonist, then preparation can be determined by detecting directly.The description of testing program:
In the RPMI1640 substratum that is supplemented with 10% foetal calf serum and 50 mcg/ml gentamicins, cultivate the JY cell.At 37 ℃, 5% CO 2In the atmosphere, under 95% relative humidity, cultivate this cell.With the RPMI1640 substratum that contains 5mM HEPES buffer reagent wash in this test employed JY cell twice and resuspending to become concentration be 2 * 10 6Cells/ml.Adding 50 microlitres are diluted in the test compound in the perfect medium in flat 96 hole microtiter plates, 50 microlitres contain or do not contain the perfect medium (being respectively applied for the feminine gender and the positive control of inhibition) of monoclonal antibody purification, and perfect medium and 100 microlitres concentration in perfect medium that 50 microlitres contain 200 millimicro grams per milliliter Buddhist ripple ester Buddhist ripple myristate acetic ester (PMA) are 2 * 10 6The cell of cells/ml.The ultimate density that obtains is 50 millimicro grams per milliliter PMA and 2 * 10 5Cells/well.Make the cell automatic sedimentation, in the degree of each time point record aggregate.Recording interval is from 0-4, and wherein 0 expression does not have cell to exist with the group basically; The cell of 1 expression＜25% exists with the group; The cell of 2 expressions＜50% exists with the group; The cell of 3 expressions＜75% exists with the group; The cell of 4 expressions 100% is assembled.Rothlein, R.R.; Deng people's " The Journal of Experimental Medicine ", 1986,163,1132-1149 discloses this method.The document has reported that also the antibody to LFA-1 can suppress accumulative formation.And when not having LFA-1 antibody to exist, 100% cell forms to be assembled, and in same document, when adding anti-LFA-1 antibody, finds to be lower than 20% cell and forms and assemble.
Data are by concentration or concentration range (μ M) record, and wherein 50% combination is suppressed.
Determine the purpose of the test test of inhibition mixed lymphocyte reacion:
As discussed above, ICAM-1 is interacting necessary by the effective cell during the immunne response of LFA-1 dependent cell adhesion mediation.When cultivating the lymphocyte of two irrelevant individualities together, observe lymphocytic protoblast and transform and cell proliferation.This replys as mixed lymphocyte reacion (MLR) is known, and with lymphocyte to replying of other antigen or mitogen similar (" immunology ": " self-science that non-self distinguishes "; Klein, J., Ed.; John Wiley ﹠amp; Sons:NY, 1982, the 453-458 pages or leaves).Monoclonal antibody at ICAM-1 and LFA-1 is used as contrast, with explanation cell adhesion dependency LS and inhibition of proliferation.
This testing program is used to the influence of determination test compound to human body MLR.Test compound suppresses ability that the monocyte of MLR and antigen-specific replys and shows that they repel and have the treatment practicality in relevant depending on aspect the interactional immune-mediated imbalance of CD18, CD11a/ICAM at acute grafing.The description of testing program:
Obtain peripheral blood by the venipuncture method from normal, healthy donor.In the test tube of heparinization, and at room temperature use Puck ' s G equilibrated salts solution (BSS) (GIBCO) to be diluted to 1: 1 blood collecting.With blood mixture fluid (20 milliliters) at 15 milliliters Ficoll/Hypaque density gradient (Pharmacia, density=1.078, room temperature) higher slice and with centrifugal 20 minutes of 1000 * gram.Collect the interface then, washing is 3 times in Puck ' s G.Counting cells and be resuspended in and contain 0.5% gentamicin on hemocytometer, in the RPMI1640 substratum (GIBCO) of the human body AB serum (sera) (ML) (RPMI substratum hereinafter referred to as) of (56 ℃, 30 minutes) of 1mM L-glutaminate (GIBCO) and 5% heat inactivation.
In Linbro round bottom microtiter plate with 6.25 * 10 5Cultivate peripheral blood monocyte (PBMC) in the substratum of cells/ml.Cultivate irritation cell from independent donor (illuminated processing so that its can not proliferating cells) with the reactor cell of same concentrations.Xiang Kongzhong adds the test compound of various concentration.Cumulative volume in each substratum is 0.2 milliliter.Contrast comprises one compound carrier (DMSO), one reactor cell and one irritation cell.Under 37 ℃, at 5%CO 2This plate of incubation is 5 days in the air atmosphere of humidification.To last 18 hours of substratum with 0.5 μ Ci contain the tritium thymidine ( 3HT) (New England Nualcar New England nuclear) adds pulse.In some cases, carry out the MLR of dual mode.This scheme is identical, and just second kind of donorcells is without the irradiation inactivation.
Adopt automatic many sample collections machine (Skatron, Norway) with cell collection in glass fibre filter, water and methanol rinse.Strainer is dry in baking oven, in Aquasol, in Beckman (LS-3801) liquid scintillation counter, count.
Data are represented with "+" or "-" by given concentration (μ M).
In vivo: allos Transplanted cells model trial purpose:
The ability of other cell that cell recognition is come by self or by other gene Different Individual (non-self) is to keep a tissue and a complete key property of organ structure.It is an important model that the allogenic cells transplanting is replied research transplant rejection and immunocompetence.This T-cell-mediated immune responses can be in adult mice be induced from the lymphocyte of histoincompatibility mouse bacterial strain by injection in pawl.This is replied and is characterised in that T-cell proliferation, this propagation are limited to from the lymphoglandula of accepting the basin of injecting the pawl zone.In vitro system, can not fully duplicate this replying in vivo.Therefore, this zootype can be used to test the ability that test compound suppresses transplant rejection.The description of testing program:
Adopt male or female mice (20-26 gram) is tested.The mouse bacterial strain of any histoincompatiblity is enough to as donor and acceptor colony.Common DBA mouse is used as donor and the C57b1/6 mouse is used as acceptor.Before use, keep according to animal source center S.O.P animal for some time during in, need stable and regulated at least 1 week.36 acceptor mouse that are divided into 6 groups are used in each research.About 4 days of test duration.Use CO 2Suffocate and kill donor mice, remove spleen, make cell suspending liquid.With this cell (1.0 * 10 7/ metatarsal, 0.05 milliliter) intradermal injection (according to standard scheme) in the back side metatarsal of acceptor mouse, after 4 days, use CO 2The kill animals of suffocating, Chu Qu popliteal knot is also weighed.At last hour of cell of injection, to the mouse group of the immunosuppressor of accepting to infer carry out subcutaneous, intraperitoneal or oral administration and after every day by standard scheme.Si Shi (Studenit) T test be used for measuring the untreated mice group and with the notable difference of the lymphonodi poplitei between those mouse of inferring the immunosuppressor processing (referring to Kroczek, R.A.; Black, C.D.V.; Barbet, J.; Shevach, E.M., " IMMUNOLOGY KEY WORDS INDEX, 1987,139,3597).
Data are by observing 50% inhibition dosage and giving the mode record of drug compound.In table 23, used following symbol: aThe nd=undetermined. bInhibition percentage at 160 mcg/ml places. cDo not observe inhibition up to maximal dose.Since the intrinsic toxicity of compound always can not be accurately quantitatively (referring to MTT result). dSuppress percentage (concentration is by μ M). eProximate incomplete dosage-response curve. FUndetermined; Compound is the synthetic intermediate.
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9 ????10 ????11 ????12 ????1.64 ????14.4 ????3.00 ????9.32 ????15.4 ????12.8 ????1.33 ????2.86 ????7.87 ????0.19 ????6.30 ????1.75 ????nd ??125-250 ??125-250 ??250-500 ??250-500 ??250-500 ??250-500 ??125-250 ??250-500 ??＞500 ????nd ??125-250 ????nd ??＞100 c????nd ????nd ????nd ????nd ????50-100 ????nd ????nd ????50 ????nd ????nd ????nd ??＞100 c????nd ????nd ????nd ????nd ???No?inh c????nd ????nd ???No?inh c????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????6.3 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????13 ????14 ????15 ????16 ????17 ????18 ????19 ????20 ????21 ????22 ????23 ????24 ????1.96 ????12.7 ????2.3 ????0.85 ????3.01 ????0.76 ????0.76 ????1.76 ????0.69 ????0.40 ????0.77 ????0.85 ????nd ??125-250 ??125-250 ??63-125 ????125 ??125-250 ????nd ??125-250 ??125-250 ??125-250 ??50-100 ???＞400 ????nd ????63-125 ????31-63 ????19-38 ????＞63 c????32-63 ????nd ????16 ????＜16 ????＜16 ????25-50 ????＞60 ????nd ????＞125 c????No?Inh c????＞75 c????No?inh c????＞125 c????nd ????63-125 ????125-250 ????No?inh c????＞100 c????No?inh c ????nd ????nd ????25-50 ????nd ????nd ????6 ????nd ????nd ????nd ????nd ????13 ????nd ????nd ????nd ????- ????nd ????nd ????- ????nd ????nd ????- ????- ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????25 ????26 ????27 ????28 ????29 ????30 ????31 ????32 ????33 ????34 ????35 ????36 ????3.08 ????2.75 ????52 e????2.59 ????0.06 ????1.48 ????1.36 ????12.1 ????0.94 ????0.13 ????0.10 ????4.05 ????nd ????nd ????nd ??100-200 ??63-125 ????nd ????nd ????nd ????nd ?200-400 ??38-46 ????nd ????nd ????nd ????nd ????100-200 c????8 ????nd ????nd ????nd ????nd ????6 ????5-10 ????nd ????nd ????nd ????nd ????No?inh c????No?inh c????nd ????nd ????nd ????nd ????No?inh c????No?inh c????nd ????nd ????nd ????nd ????nd ????0.1 ????nd ????nd ????nd ????nd ????1.8 ????0.8 ????nd ????nd ????nd ????nd ????nd ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??～60(per?os) ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????37 ????38 ????39 ????40 ????41 ????42 ????43 ????44 ????45 ????46 ????47 ????48 ????0.16 ????1.15 ????0.18 ????0.48 ????0.16 ????0.60 ????0.17 ????0.42 ????nd f????2.26 ????4.31 ????1.75 ????＜13 ????nd ????nd ????50-100 ????nd ????nd ????25-50 ????63-125 ????nd ????nd ????nd ????nd ????5-10 ????nd ????nd ????50-100 ????nd ????nd ????3-6 ????6-12 ????nd ????nd ????nd ????nd ????＞19 ????nd ????nd ????50-100 ????nd ????nd ????No?inh c????No?inh c????nd ????nd ????nd ????nd ????1.6 ????nd ????nd ????25 ????nd ????nd ????1.8 ????0.3 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????49 ????50 ????51 ????52 ????53 ????54 ????55 ????56 ????57 ????58 ????59 ????60 ????0.26 ????17 e????0.43 ????1.59 ????1.47 ????0.42 ????0.20 ????0.48 ????0.36 ????2.85 ????0.33 ????0.23 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with mensuration ' K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????61 ????62 ????63 ????64 ????65 ????66 ????67 ????68 ????69 ????70 ????71 ????72 ????2.35 ????0.16 ????3 e????1.45 ????1.32 ????2.85 ????3.54 ????2.58 ????70 e????1.89 ????4.38 ????0.06 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??＞363 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????20-40 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????No?inh c ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????1.4 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?73 ?74 ?75 ?76 ?77 ?78 ?79 ?80 ?81 ?82 ?83 ?84 ????0.34 ????0.67 ????0.29 ????2.34 ????nd f????0.34 ????0.43 ????0.19 ????0.08 ????2.1 ????0.30 ????0.42 ????nd ????nd ????nd ????＞500 ????nd ????nd ????nd ????＞400 ??25-50 ??250-500 ??250-500 ????nd ????nd ????nd ????nd ????150-300 ????nd ????nd ????nd ????5 ????1-3 ????63-125 ????13-25 ????nd ????nd ????nd ????nd ????＞300 c????nd ????nd ????nd ????No?inh c????No?inh c????＞250 c????＞200 c????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????3.2 ????6.3 ????nd ????6 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????85 ????86 ????87 ????88 ????89 ????90 ????91 ????92 ????93 ????94 ????95 ????96 ????0.72 ????0.53 ????2.00 ????0.41 ????0.29 ????0.73 ????0.43 ????0.12 ????1.27 ????0.74 ????0.26 ????0.46 ????＞500 ????＞500 ????＞500 ????250-500 ????500 ????＞500 ????nd ????63-125 ????100-200 ????200 ????nd ????100-200 ????19-38 ????19-38 ????50-100 ????19-38 ????50 ????50-100 ????nd ????13-25 ????＞100 c????50-100 ????nd ????50 ????＞75 c????＞75 c????＞100 c????＞75 c????No?inh c????No?inh c????nd ????No?inh c????No?inh c????No?inh c????nd ????No?inh c ????nd ????nd ????50 ????nd ????nd ????nd ????nd ????3.1 ????13 ????25 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????97 ????98 ????99 ????100 ????101 ????102 ????103 ????104 ????105 ????106 ????107 ????108 ????0.023 ????0.055 ????0.52 ????0.19 ????0.68 ????0.06 ????0.10 ????0.27 ????0.12 ????0.14 ????0.49 ????0.41 ????＞350 ????＞340 ????nd ????＞400 ????nd ????＞400 ????25-50 ????nd ????nd ????nd ????nd ????nd ????5-10 ????5-10 ????nd ????8-15 ????nd ????25-50 ????25 ????nd ????nd ????nd ????nd ????nd ????No?inh c????No?inh c????nd ????＞60 ????nd ????＞200 ????＞25 ????nd ????nd ????nd ????nd ????nd ????2 ????3 ????nd ????0.7 ????nd ????1.3 ????0.13 ????nd ????nd ????nd ????nd ????nd ??+(25-50) ????+(50) ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??～25per?os ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
????109 ????110 ????111 ????112 ????113 ????114 ????115 ????116 ????117 ????118 ????119 ????120 ????0.03 ????0.15 ????0.19 ????0.39 ????1.91 ????0.26 ????.024 ????0.19 ????1.09 ????0.46 ????0.02 ????0.48 ?100-200 ?200-400 ????36 ????nd ????nd ????nd ????nd ????nd ????12 ?200-400 ??＞400 ????nd ????3-6 ????25 ????3 ????nd ????nd ????nd ????nd ????nd ????12 ??＞100 ??＜3 ????nd ????No?inh c????No?inh c????No?inh c????nd ????nd ????nd ????nd ????nd ????12 ??＞100 ????No?inh c????nd ????0.4 ????9 ????75 ????nd ????nd ????nd ????nd ????nd ????2.2 ????3.4 ????0.05 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??121 ??122 ??123 ??124 ??125 ??126 ??127 ??128 ??129 ??130 ??131 ??132 ????0.21 ????0.13 ????0.10 ????0.03 ????0.11 ????0.81 ????0.05 ????0.16 ????0.10 ????0.33 ????0.20 ????0.22 ????＜11 ??200-400 ??50-100 ??100-200 ????＞400 ????nd ??125-250 ??125-250 ????nd ????nd ????＞400 ??200-400 ????0.8-2 ????12-25 ????12-25 ????1.5 ????1-3 ????nd ????0.8-1.6 ????1.5 ????nd ????nd ????3-5 ????5 ????No?inh c????No?inh c????＞25 ????No?inh c????No?inh c????nd ????No?inh c????No?inh c????nd ????nd ????No?inh c????No?inh c ????25 ????1.8 ????0.6 ????0.1 ????0.4 ????nd ????0.1 ????0.1 ????nd ????nd ????1.1 ????2.4 ????nd ????nd ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??～90per?os ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?133 ?134 ?135 ?136 ?137 ?138 ?139 ?140 ?141 ?142 ?143 ?144 ????0.15 ????0.05 ????0.20 ????0.19 ????0.04 ????0.04 ????0.79 ????0.11 ????0.22 ????0.43 ????1.20 ????0.35 ???＞400 ???＞250 ???＞400 ??150-300 ??200-400 ??250-500 ????nd ??180-360 ????300 ????nd ????nd ????nd ????5-10 ????1.5 ????25 ????0.6-1 ????1-3 ????6 ????nd ????1.2 ????15 ????nd ????nd ????nd ????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c????nd ??＞10 ??＞15 ????nd ????nd ????nd ????0.4 ????0.1 ????1.7 ????nd ????0.4 ????nd ????nd ????0.2 ????0.1 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??+(25-50) ????nd ????nd ????- ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??145 ??146 ??147 ??148 ??149 ??150 ??151 ??152 ??153 ??154 ??155 ??156 ????1.05 ????0.13 ????0.34 ????0.50 ????0.20 ????0.51 ????0.046 ????2.66 ????2.19 ????0.094 ????0.51 ????0.69 ????nd ????100 ????nd ????nd ??170-340 ????nd ??＞410 ????nd ????nd ????200 ????nd ????nd ????nd ????13-25 ????nd ????nd ????10 ????nd ????5-10 ????nd ????nd ????5-10 ????nd ????nd ????nd ????No?inh c????nd ????nd ??＞10 ????nd ????No?inh c????nd ????nd ????No?inh c????nd ????nd ????nd ????0.4 ????nd ????nd ????2.9 ????nd ????0.2 ????nd ????nd ????0.4 ????nd ????nd ????nd ????+(50) ????nd ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?157 ?158 ?159 ?160 ?161 ?162 ?163 ?164 ?165 ?166 ?167 ?168 ????0.037 ????0.69 ????0.11 ????0.64 ????4.56 ????1.05 ????0.16 ????0.28 ????1.07 ????0.28 ????0.60 ????0.41 ??＞390 ????nd ????50-100 ????nd ????nd ????nd ??200-400 ??100-200 ????nd ????nd ????nd ????nd ????5-10 ????nd ????10-20 ????nd ????nd ????nd ????9-19 ??＞100 c????nd ????nd ????nd ????nd ????No?inh c????nd ????No?inh c????nd ????nd ????nd ??＞75 c????No?inh c????nd ????nd ????nd ????nd ????0.4 ????nd ????2 ????nd ????nd ????nd ????2.4 ????25 ????nd ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The Ex. of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
????ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??169 ??170 ??171 ??172 ??173 ??174 ??175 ??176 ??177 ??178 ??179 ??180 ????0.05 ????0.02 ????0.18 ????0.17 ????0.17 ????0.71 ????0.23 ????3.96 ????0.25 ????1.17 ????3.84 ????0.19 ??160-230 ????nd ??100-200 ????165 ??200-400 ????nd ????nd ????nd ??155-310 ????nd ????nd ?200-400 ????12-25 ????nd ????102 ????1.8 ????4.8 ????nd ????nd ????nd ????7-14 ????nd ????nd ????1.5-3 ????No?inh c????nd ????No?inh c????No?inh c????No?inh c????nd ????nd ????nd ????No?inh c????nd ????nd ????No?inh c ????1.5 ????nd ????0.2 ????0.7 ????2.2 ????nd ????nd ????nd ????3.7 ????nd ????nd ????1.3 ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) FI fibronectin IC 50(μM)
??181 ??182 ??183 ??184 ??185 ??186 ??187 ??188 ??189 ??190 ??191 ??192 ????47％ b????0.05 ????0.94 ????0.37 ????0.25 ????1.11 ????0.29 ????0.04 ????0.19 ????0.43 ????0.14 ????1 e ????nd ??200-400 ????nd ??50-100 ????nd ????nd ????171 ??56-112 ????63 ??50-100 ????nd ????nd ????nd ????3-6 ????nd ????0.8-1.5 ????nd ????nd ????0.6 ????0.3-1 ????0.6-1.2 ????6-12 ????nd ????nd ????nd ????No?inh c????nd ????No?inh c????nd ????nd ????No?inh c????No?inh c????No?inh c????No?inh c????nd ????nd ????nd ????0.02 ????nd ????0.3 ????nd ????nd ????0.6 ????0.03 ????nd ????1.4 ????nd ????nd ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) FIBRONECTIN ??IC 50(μM)
????193 ????194 ????195 ????196 ????197 ????198 ????199 ????200 ????201 ????202 ????203 ????204 ????0.29 ????0.27 ????0.30 ????0.09 ????0.19 ????0.14 ????0.27 ????0.09 ????0.68 ????0.23 ????0.34 ????0.50 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??205 ??206 ??207 ??208 ??209 ??210 ??211 ??212 ??213 ??214 ??215 ??216 ????0.56 ????0.73 ????1.28 ????0.65 ????0.94 ????0.54 ????2 e????0.07 ????2 e????0.09 ????0.20 ????0.50 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??100-200 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????50-100 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ??＞100 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????3.1 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
????ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?217 ?218 ?219 ?220 ?221 ?222 ?223 ?224 ?225 ?226 ?227 ?228 ????1.78 ????0.80 ????1.03 ????0.27 ????0.14 ????0.06 ????0.15 ????0.28 ????0.63 ????0.07 ????0.18 ????0.41 ????nd ????nd ????nd ????nd ????nd ????nd ??200-400 ??＜25 ??50-100 ????100 ??200-400 ??50-100 ????nd ????nd ????nd ????nd ????nd ????nd ????2-4 ????5-10 ????3-4 ????3-6 ????25 ????12-25 ????nd ????nd ????nd ????nd ????nd ????nd ????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c ????nd ????nd ????nd ????nd ????nd ????nd ????0.2 ????3.1 ????0.2 ????1.6 ????3.1 ????1.6 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????+(25) ????+(25) ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?229 ?230 ?231 ?232 ?233 ?234 ?235 ?236 ?237 ?238 ?239 ?240 ????0.30 ????2.20 ????0.27 ????1.24 ????1.79 ????0.41 ????0.33 ????0.33 ????0.13 ????0.08 ????0.28 ????0.11 ??50-100 ????nd ????40-80 ????nd ????nd ??100-200 ??100-200 ????nd ??50-100 ????nd ????nd ????11-23 ????6-13 ????nd ????2-5 ????nd ????nd ????5-10 ????9 ????nd ????1-2 ????nd ????nd ????1-3 ????No?inh c????nd ????No?inh c????nd ????nd ????No?inh c????No?inh c????nd ????No?inh c????nd ????nd ????13.4 ????3.1 ????nd ????nd ????nd ????nd ????1.6 ????1.6 ????nd ????0.1 ????nd ????nd ????6.3 ????+(50) ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
?241 ?242 ?243 ?244 ?245 ?246 ?247 ?248 ?249 ?250 ?251 ?252 ????0.10 ????0.40 ????0.11 ????3.98 ????0.21 ????0.25 ????0.23 ????0.37 ????0.16 ????0.04 ????0.06 ????0.11 ????9-18 ????16-32 ????10-20 ????200-400 ????25-50 ????nd ????40-80 ????50-100 ????200-400 ????100-200 ????100-200 ????17-20 ????0.8-1.6 ????10-25 ????5-6 ????4-8 ????1-3 ????nd ????1.5-3 ????9-18 ????＜1 ????＜1 ????＜0.5 ????0.4-0.8 ????13 ????No?inh c????No?inh c????No?inh c????No?inh c????nd ????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c ????nd ????2.8 ????3.1 ????2.2 ????0.7 ????nd ????2.3 ????0.7 ????0.4 ????0.1 ????nd ????0.3 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??253 ??254 ??255 ??256 ??257 ??258 ??259 ??260 ??261 ??262 ??263 ??264 ????0.05 ????0.08 ????0.14 ????0.12 ????0.08 ????1.66 ????3.54 ????0.07 ????nd f????0.08 ????0.09 ????0.12 ??100-200 ??100-200 ??100-200 ??150-300 ????300 ????nd ????nd ??200-400 ????nd ??25-75 ??20-40 ??12-24 ????1-2 ????1-2 ????1 ????0.8-2 ????1.6 ????nd ????nd ????19-38 ????nd ????1-2 ????0.8-1.6 ????2-5 ????No?inh c????No?inh c????No?inh c????No?inh c????No?inh c????nd ????nd ????No?inh c????nd ????No?inh c????No?inh c????No?inh c ????0.2 ????0.4 ????0.2 ????0.4 ????0.6 ????nd ????nd ????1.1 ????nd ????0.4 ????0.8 ????0.4 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the Transplanted cells of A allos 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??265 ??266 ??267 ??268 ??269 ??270 ??271 ??272 ??273 ??274 ??275 ??276 ????0.28 ????0.14 ????0.40 ????1.59 ????0.29 ????0.65 ????0.02 ????0.56 ????0.19 ????0.14 ????2.00 ????1.11 ??130-250 ??＞500 ????250 ??250-500 ??250-500 ??250-500 ??250-500 ??250-500 ??150-300 ??200-300 ????nd ????375 ????19-38 ????25-50 ????nd ????nd ????25 ????nd ????3 ????50-100 ????38 ????25-50 ????nd ????10 ??＞75 c??＞50 c????nd ????nd ????No?inh c????nd ????No?inh c????No?inh c??＞75 c??＞100 c????nd ????No?inh c ????3 ????3 ????nd ????nd ????nd ????nd ????0.1 ????nd ????2 ????3 ????nd ????0.5 ????nd ??+(25-50) ????nd ????nd ????nd ????nd ??+(13-25) ????nd ?????- ?????- ????nd ????+(25) ????nd ????nd ????nd ????nd ????nd ????nd ??～20(per?os) ????nd ????nd ????nd ????nd ????nd
Table 23. biological test result
The compound of embodiment LFA-1/ICAM is in conjunction with measuring K d(μM) Cell toxicity test MTT LD 50(μM) The mensuration that detects the SKW3 cell is attached to JY cell IC50 (μ M) is measured in JY cell aggregation Mixed lymphocyte reacion MLR+/-(μ M) ACT ED is measured in the allos Transplanted cells 50(mg/kg)
??ICAM ?IC 50(μM) Fibronectin IC 50(μM)
??277 ??278 ????0.07 ????1.09 ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd ????nd
The description of therepic use
Novel and the known small molecules of using has in the methods of the invention suppressed the ICAM-1/LFA-1 dependency homotypic aggregation of human lymphocyte, and the adhesion of human lymphocyte and ICAM-1 and human lymphocyte are replied antigenic.These compounds have therepic use aspect activity/propagation between the adjusting immunocyte, for example as comprising the competitive inhibitor of CAMs with the iuntercellular ligand/receptor association reaction of white integrin.The inflammatory disease of the available compounds for treating that the present invention includes comprises because of the disease that non-specific immunity system replying in mammal causes (adult respiratory distress syndrome for example, shock, oxygen intoxication, multiple organ injury's syndromes of septicemia secondary, multiple organ injury's syndromes of wound secondary, tissue reperfusion damage because of cardiopulmonary bypass, the use of myocardial infarction or Actosolv, acute glomerulonephritis, vasculitis, reactive arthritis, the tetter of acute inflammation part, apoplexy, thermal damage, hemodialysis, white corpuscle is removed (leukapheresis), ulcerative colitis, cause the syndromes of downright bad enterocolitis and granulocyte transfusion association) and the disease that causes by specific immune system replying in Mammals (psoriasis for example, the organ-/ tissue transplant rejection, graft is to host's reaction and autoimmune disorders, comprise the Reynolds (syndromes of Raynaud ' s), the autoimmunity thyroiditis, dermatitis, multiple sclerosis, rheumatosis sacroiliitis, insulin-dependent diabetes, uveitis, inflammatory bowel disease, comprise Crohn disease and ulcerative colitis and whole body lupus erythematosus).According to the present invention, these are novel and known compound also can be used for treatment asthma or will use the toxicity of cytokinin (cytokine) therapy to reduce to minimum in the treatment cancer.Usually these compounds can be used in those diseases that treatment is treated by Steroid treatment at present.
According to method provided by the invention, these novel and compound known can be to " prevention " or " treatment " purpose with independent or with other immunosuppressor or anti-inflammatory agent administration.
When with the administration of " prevention " purpose, any inflammatory response or symptom (for example before organ or tissue transplants, during or afterwards soon but before the symptom any organ rejection) administration before is with described immunosuppressive compounds.The effect of the compound of preventive administration formula I is prevention or weakens any inflammatory response (for example the repulsion of transplant organ or tissue etc.) subsequently.The effect of therapeutic Medicine-feeding type I compound is the inflammation (for example repulsion of transplant organ or tissue) that weakens any reality.Therefore, according to the present invention, the compound of formula I can begin preceding administration (purpose is the inflammation that suppresses to occur in advance) or begin the back administration in inflammation in inflammation.
According to the present invention, the novel and known compound of formula I can be disposable or divided dose carry out oral, parenteral or topical.The oral dosage of suitable formula I compound is about 0.5 milligram-1 gram/sky.In parenteral administration, suitable dose can be the described compound of 0.1-250 milligram, and during topical, the contained active ingredient of preparation is preferably 0.01-1%.But should be clear: patient and patient's dosage will change, and for any concrete patient, dosage will depend on clinical diagnosis, and the standard of determining suitable dosage is patient's age and situation and patient's replying medicine.
When oral administration compound of the present invention, medicine type administration that can pharmaceutical preparation, described medicament contains compound and relevant compatible pharmaceutical carrier.This class carrier substance can be to be suitable for oral inertia organic or inorganic carrier substance.The example of this class carrier substance is water, gelatin, talcum, starch, Magnesium Stearate, Sudan Gum-arabic, vegetables oil, polyalkylene glycol, Vaseline etc.
Pharmaceutical preparation can prepare according to a conventional method, and final dosage form can be the solid dosage form, for example tablet, drageeing, capsule etc., or liquid dosages form, for example solution, suspension, emulsion etc.Pharmaceutical preparation can be carried out conventional drug treating for example sterilizes.In addition, pharmaceutical preparation can contain for example salt etc. of sanitas, stablizer, emulsifying agent, flavour improving agent, wetting agent, buffer reagent, change osmotic pressure of conventional auxiliary agent.Spendable solid carrier material comprises for example starch, lactose, mannitol, methylcellulose gum, Microcrystalline Cellulose, talcum, silicon-dioxide, monocalcium phosphate and high-molecular weight polymer (for example polyoxyethylene glycol).
For the administered parenterally form, the compound of formula I can the aqueous solution or suspension or the emulsion or the mixtures of liquids form administration of non-aqueous solution, acceptable oil, and they can contain fungistat, antioxidant, sanitas, buffer reagent or make solution and hemisotonic other solute, thickening material, suspension agent or other pharmaceutically acceptable additive.Such additive comprises that for example tartrate, citric acid and acetic acid buffer, ethanol, propylene glycol, polyoxyethylene glycol, title complex form agent (for example EDTA), antioxidant (for example sodium pyrosulfate, sodium metabisulfite and xitix), the high-molecular weight polymer (for example liquid polyethylene oxide) that is used to regulate viscosity and the polythene derivative of sorbitan.Also can add sanitas in case of necessity, for example phenylformic acid, nipagin or propylparaben, Zephiran chloride and other quaternary ammonium compound.
The solution form administration that compound of the present invention also can nose uses except compound of the present invention, also can contain the antioxidant and the tackifier of suitable reducing, tension regulator, microbiological antiseptic, vehicle aqueous solution form.The example that is used to improve the additive of viscosity is polyvinyl alcohol, derivatived cellulose, polyvinylpyrrolidone, Spheron MD 30/70 or glycerine.The microbiological antiseptic that adds can comprise, Zephiran chloride, thimerosal, butylene-chlorohydrin or styroyl alcohol.
In addition, the form administration that compound of the present invention can suppository.Preparation
Can be by any means the compound of formula I be mixed with medicine.Several exemplary preparations are described below.Embodiment A capsule or tablet
Embodiment A-1 Embodiment A-2
Amounts of components Amounts of components
1 milligram of 2 milligrams of smog colloidal silica of 10 milligrams of Magnesium Stearates of 90 milligrams of sodium starch glycollates of 160 milligrams of Microcrystalline Celluloses of 250 milligrams of starch of formula I compound 1 milligram of 10 milligrams of smog colloidal silica of 5 milligrams of sodium starch glycollates of 90 milligrams of stearic acid of 160 milligrams of Microcrystalline Celluloses of 50 milligrams of Lin Suanergais of formula I compound
The compound of formula I is mixed with the excipient material of premixed said components (except the lubricant), make powdered mixture.Sneak into lubricant then, institute is formed mixture be pressed into tablet or be loaded in the hard gelatine capsule.The Embodiment B parenteral solution
Component Consumption
Formula I Compound P EG400 ethanol salt solution 500 milligram of 40% volume 5% volume 55% volume
The admixed excipients material adds a kind of compound of formula I then, and its volume need reach dissolving.Continue to mix transparent up to solution.Filtering solution is sterilized in suitable bottle or ampoule and through autoclave then.Embodiment C suspension
Component Consumption
Formula I compound citric acid Zephiran chloride EDTA polyvinyl alcohol water 100 milligram of 1.92 gram 0.025% weight 0.1% weight 10% weight is added to 100 milliliters
Excipient material is mixed with water, add a kind of compound of formula I then, continue to mix even up to suspension.Suspension is transferred in the suitable bottle or ampoule then.

Claims (17)

1. the method for disease of treatment or preventing inflammation or immunocyte mediation, described method comprises the formula I compound or pharmaceutically acceptable salt thereof of administration prevention or therapeutic dose:
Wherein:
Y is oxygen or sulphur atom;
Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced or polysubstituted by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, the peaceful base of phthalein (pthalaninyl), quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be substituted by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or wherein, R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R wherein 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
Figure A9880301200031
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R wherein 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
Figure A9880301200041
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200042
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Figure A9880301200051
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
(I) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(x) cyano group, or
(xi) amidino groups of following formula
Figure A9880301200061
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
R 2Be:
(A) hydrogen atom, or
(B) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom, wherein said alkyl or cycloalkyl can randomly be replaced by following groups:
(i) formula-OR 34Group, R wherein 34Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(ii) formula-NR 35R 36Group, R wherein 35And R 36Be hydrogen atom independently respectively, have the alkyl of 1-2 carbon atom or have the acyl group of 1-2 carbon atom;
R 3Be-(CR 37R 38) x(CR 39R 40) yR 41Group, wherein
X and y are respectively 0 or 1 independently,
R 37, R 38And R 39Be independently respectively:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
R 40Be:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(D) aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) R 43It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group that 6-or 7-quinazolyl are formed
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 44Group, R wherein 44Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 45R 46Group, R wherein 45And R 46Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 45And R 46Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 47R 48Group, R wherein 47And R 48Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 47And R 48Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 49Group, R wherein 49Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 50Group, R wherein 50Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(j) cyano group,
(k) nitro,
(l) amidino groups of following formula
R wherein 51, R 52And R 53Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 51, R 52And R 53In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(m) halogen,
(ii) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 43The single replacement,
(iii) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(iv) formula-COOR 54Group, R wherein 54Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(v) formula-NR 55R 56Group, R wherein 55And R 56Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 55And R 56Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 55And R 56In a group can be radicals R in addition 43,
(vi) formula-CONR 57R 58Group, R wherein 57And R 58Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 57And R 58Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 57And R 58In a group can additionally be radicals R 43,
(vii) formula-COR 59Group, R wherein 59Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 43,
(viii) formula-OR 60Group, R wherein 60Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 43,
(ix) formula-SR 61Group, R wherein 61Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 43,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently;
2. the compound or pharmaceutically acceptable salt thereof of formula I:
Wherein:
Y is oxygen or sulphur atom;
Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced or polysubstituted by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
Figure A9880301200141
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
Figure A9880301200151
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Figure A9880301200161
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
(I) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(x) cyano group, or
(xi) amidino groups of following formula
Figure A9880301200171
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
R 2Be:
(A) hydrogen atom, or
(B) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom, wherein said alkyl or cycloalkyl can randomly be replaced by following groups:
(i) formula-OR 34Group, R wherein 34Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(ii) formula-NR 35R 36Group, R wherein 35And R 36Be hydrogen atom independently respectively, have the alkyl of 1-2 carbon atom or have the acyl group of 1-2 carbon atom;
R 3Be-(CR 37R 38) x(CR 39R 40) yR 41Group, wherein
X and y are respectively 0 or 1 independently,
R 37, R 38And R 39Be independently respectively:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
R 40Be:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(D) aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) R 43It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 44Group, R wherein 44Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 45R 46Group, R wherein 45And R 46Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 45And R 46Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 47R 48Group, R wherein 47And R 48Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 47And R 48Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 49Group, R wherein 49Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 50Group, R wherein 50Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) nitro,
(l) amidino groups of following formula
Figure A9880301200201
R wherein 51, R 52And R 53Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 51, R 52And R 53In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(m) halogen,
(ii) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 43The single replacement,
(iii) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(iv) formula-COOR 54Group, R wherein 54Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(v) formula-NR 55R 56Group, R wherein 55And R 56Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 55And R 56Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 55And R 56In a group can additionally be radicals R 43,
(vi) formula-CONR 57R 58Group, R wherein 57And R 58Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 57And R 58Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 57And R 58In a group can additionally be radicals R 43,
(vii) formula-COR 59Group, R wherein 59Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 43,
(viii) formula-OR 60Group, R wherein 60Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 43,
(ix) formula-SR 61Group, R wherein 61Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 43,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
At least one hydrogen atom of wherein said aryl is replaced by following groups:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
Figure A9880301200221
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently.
3. according to the compound or pharmaceutically acceptable salt thereof of the formula I of claim 2, wherein:
Y is oxygen or sulphur atom;
Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
Figure A9880301200251
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200262
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group randomly can be replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(the sulfonic acid group that v) has 1-6 carbon atom;
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently.
4. according to the formula I compound or pharmaceutically acceptable salt thereof of claim 3, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl, be selected from phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NH 2Group,
(g) formula-CONH 2Group,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(i) amidino groups of following formula
Figure A9880301200311
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(iii) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(iv) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(the v) quaternary group of following formula
Figure A9880301200312
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200313
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Figure A9880301200321
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62It is aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be methyl,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be respectively hydrogen atom or methyl independently,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be respectively hydrogen atom or methyl independently,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or methyl,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be respectively hydrogen atom or methyl independently, and R wherein 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively hydrogen atom or methyl independently, and R wherein 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, methyl or R 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl;
R 5It is hydrogen atom; With
R 6Be Cl or trifluoromethyl.
5. according to the formula I compound or pharmaceutically acceptable salt thereof of claim 4, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl and triazinyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NH 2Group,
(g) formula-CONH 2Group,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(i) amidino groups of following formula
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(iii) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(iv) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(the v) quaternary group of following formula
Figure A9880301200351
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200352
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Figure A9880301200353
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom,
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl is selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyridazinyl and pyrazinyl,
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyridazinyl and pyrazinyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii) formula-COOR 63Group, R wherein 63Be methyl,
(iv) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl,
(v) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively methyl, and R wherein 76And R 77In a group be methyl, another group is R 62,
(F) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(G) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(H) cyano group,
(I) nitro, or
(J) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be Cl or trifluoromethyl.
6. according to the formula I compound or pharmaceutically acceptable salt thereof of claim 5, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl is selected from the group of phenyl or pyridyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl,
(f) amidino groups of following formula
Figure A9880301200381
R wherein 13, R 14And R 15Be respectively hydrogen atom,
(iii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
The (iv) quaternary group of following formula
Figure A9880301200382
R wherein 24, R 25And R 26Be respectively methyl and Q -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Figure A9880301200383
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom,
(G) guanidine radicals of following formula
Figure A9880301200391
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom, or
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom,
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Aryl is selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii)-COOH，
(iii) formula-COOR 63Group, R wherein 63Be methyl,
(iv) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(v) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by fluorine or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be methyl,
(E) formula-CONR 76R 77Group, R wherein 76And R 77Be respectively methyl, and R wherein 76And R 77In a group be methyl, another group is R 62,
(F) formula-COR 78Group, R wherein 78Be hydrogen atom, methyl or R 62,
(G) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(H) cyano group,
(I) nitro, or
(J) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
7. according to the formula I compound or pharmaceutically acceptable salt thereof of claim 6, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞CHR 1Or＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) have the alkyl of 1-2 carbon atom, described alkyl can be replaced by following groups is single:
(i) oxygen,
(ii) aryl is selected from the group of phenyl or pyridyl
A hydrogen atom of wherein said aryl can randomly be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or methyl, or
(f) amidino groups of following formula R wherein 13, R 14And R 15Be respectively hydrogen atom, or (iii) formula-OR 19Group, R wherein 19Be hydrogen atom or methyl, (C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom, (D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom, (E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom, (F) amidino groups of following formula Wherein r is 2,3,4,5 or 6 and R wherein 27, R 28And R 29Be respectively hydrogen atom, or (G) guanidine radicals of following formula
Figure A9880301200412
Wherein s is 2,3,4,5 or 6, and R 30, R 31, R 32And R 33Be respectively hydrogen atom, R 2Be: (A) hydrogen atom, or (B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) formula-COOR 63Group, R wherein 63Be methyl,
(iii) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(iv) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted or can be by R 62The single replacement,
(C) formula-COOR 73Group, R wherein 73Be methyl,
(D) formula-COR 78Group, R wherein 78Be methyl or R 62,
(E) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(F) cyano group,
(G) nitro, or
(H) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
8. according to the formula I compound or pharmaceutically acceptable salt thereof of claim 7, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is formula＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) methyl or ethyl, or
(C)-COCH 3
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) formula-COOR 63Group, R wherein 63Be methyl,
(iii) formula-OR 68Group, R wherein 68Be hydrogen atom or methyl, or
(iv) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted or can be by R 62The single replacement,
(C) formula-COOR 73Group, R wherein 73Be methyl,
(D) formula-COR 78Group, R wherein 78Be methyl or R 62,
(E) formula-OR 79Group, R wherein 79Be hydrogen atom, methyl or R 62,
(F) cyano group,
(G) nitro, or
(H) halogen,
R 4Be chlorine atom or trifluoromethyl; With,
R 5It is hydrogen atom; With
R 6Be chlorine atom or trifluoromethyl.
9. formula I compound or pharmaceutically acceptable salt thereof according to Claim 8, wherein:
Y is a Sauerstoffatom;
Z is a Sauerstoffatom;
X is＞NR 1Divalent group,
R wherein 1Be:
(A) hydrogen atom,
(B) methyl or ethyl, or
(C)-COCH 3
R 2Be:
(A) hydrogen atom, or
(B) methyl;
R 3Be formula-CH 2R 41Group, wherein:
R 41Be:
Phenyl,
One or more hydrogen atoms of wherein said phenyl must and be replaced by following groups independently:
(A) R 62, be aryl, be selected from the group of phenyl or pyridyl,
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) methyl,
(ii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted,
(C) formula-COR 78Group, R wherein 78Be methyl or R 62,
(D) halogen;
R 4It is the chlorine atom;
R 5It is hydrogen atom; With
R 6It is the chlorine atom.
10. be selected from the compound or pharmaceutically acceptable salt thereof of following compound:
Figure A9880301200441
11. the disease that treatment or preventing inflammation, immunocyte cause or the method for symptom comprise that administration is with the claim 2,3,4,5,6,7,8 of preventive dose or therapeutic dose, 9 or 10 compound.
12. the method for claim 1 or 11, wherein disease or symptom are selected from: adult respiratory distress syndrome, shock, oxygen intoxication, multiple organ injury's syndromes of septicemia secondary, multiple organ injury's syndromes of wound secondary, tissue reperfusion damage because of cardiopulmonary bypass, the use of myocardial infarction or Actosolv, acute glomerulonephritis, vasculitis, reactive arthritis, the tetter of acute inflammation part, apoplexy, thermal damage, hemodialysis, white corpuscle is removed (leukapheresis), ulcerative colitis, cause the syndromes of downright bad enterocolitis and granulocyte transfusion association.
13. method according to claim 1 or 11, wherein disease or symptom are selected from psoriasis, organ-/ tissue transplant rejection, graft reaction and the autoimmune disorders to the host, comprise Reynolds syndromes, autoimmunity thyroiditis, dermatitis, multiple sclerosis, rheumatosis sacroiliitis, insulin-dependent diabetes, uveitis, inflammatory bowel disease, comprise Crohn disease and ulcerative colitis and whole body lupus erythematosus.
14. according to the method for claim 1 or 11, wherein disease or symptom comprise asthma.
15. according to the method for claim 1 or 11, wherein symptom is the toxicity relevant with the cytokinin therapeutics.
16. contain the pharmaceutical composition of pharmaceutically acceptable carrier and formula I compound
Figure A9880301200451
Wherein: Y is oxygen or sulphur atom; Z is oxygen or sulphur atom;
X is formula＞CHR 1,＞NR 1,＞CHSO 2R 1, or＞NSO 2R 1Divalent group or oxygen or sulphur atom,
R wherein 1Be:
(A) hydrogen atom,
(B) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl or cycloalkyl can be replaced or polysubstituted by following groups is single:
(i) halogen,
(ii) oxygen,
(iii) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the alkyl of 1-3 carbon atom,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) amidino groups of following formula
Figure A9880301200471
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(iv) formula-COOR 16Group, R wherein 16Be to have the straight or branched alkyl of 1-7 carbon atom or have the cycloalkyl of 3-6 carbon atom,
(v) cyano group,
(vi) formula-CONR 17R 18Group, R wherein 17And R 18Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 17And R 18Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-OR 19Group, R wherein 19Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(viii) formula-SR 20Group, R wherein 20Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-NR 21R 22Group, R wherein 21And R 22Be independently respectively
(a) hydrogen atom,
(b) have the alkyl or the acyl group of 1-7 carbon atom or have the cycloalkyl of 3-7 carbon atom,
(c) formula-(CH 2) mThe group of COOH, wherein m is 0,1 or 2, or
(d) formula-(CH 2) nCOOR 23Group, wherein n is 0,1 or 2, wherein R 23Be straight or branched alkyl with 1-6 carbon atom,
Or R 21And R 22Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(x) the quaternary group of following formula
Figure A9880301200481
R wherein 24, R 25And R 26Be respectively branched-chain or straight-chain alkyl and Q independently with 1-7 carbon atom -Be chlorine, bromine or iodine counter ion,
(C) have side chain or straight-chain carboxylic acid's group of 3-6 carbon atom,
(D) have the side chain or the straight chain phosphonyl group of 2-6 carbon atom,
(E) have the side chain or the straight chain sulfonic acid group of 2-6 carbon atom,
(F) amidino groups of following formula
Wherein r be 2,3,4,5 or 6 and
R wherein 27, R 28And R 29Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 27, R 28And R 29In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(G) guanidine radicals of following formula
Wherein s be 2,3,4,5 or 6 and
R 30, R 31, R 32And R 33Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 30, R 31, R 32And R 33In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(H) piperidyl, the nitrogen-atoms of wherein said group is randomly replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
The carboxylate group who (ii) has 2-7 carbon atom,
The hydroxy-acid group that (iii) has 2-5 carbon atom,
The phosphonyl group that (iv) has 1-6 carbon atom, or
(sulfonic acid group that v) has 1-6 carbon atom, or
(I) aryl, be selected from phenyl, naphthyl, indyl, sulfur phenenyl, pyridyl, pyrimidyl, furyl, pyrryl oxazolyl, thiazolyl, pyrazolyl isoxazolyl, imidazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, pseudoindoyl, benzo [b] furyl, benzo [b] sulfur phenenyl, indazolyl, benzothiazolyl, benzimidazolyl-, quinolyl, isoquinolyl, purine radicals, quinolizinyl, cinnolinyl, phthalein is base rather, quinoxalinyl, naphthyridinyl, the group of pteridyl and quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the alkyl of 1-3 carbon atom,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 7Group, R wherein 7Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 8R 9Group, R wherein 8And R 9Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 8And R 9Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 10R 11Group, R wherein 10And R 11Be hydrogen atom independently respectively, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 10And R 11Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 12aGroup, R wherein 12aBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 12bGroup, R wherein 12bBe hydrogen atom or alkyl or acyl group with 1-7 carbon atom,
(x) cyano group, or
(xi) amidino groups of following formula
Figure A9880301200501
R wherein 13, R 14And R 15Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 13, R 14And R 15In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
R 2Be:
(A) hydrogen atom, or
(B) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom, wherein said alkyl or cycloalkyl can randomly be replaced by following groups:
(i) formula-OR 34Group, R wherein 34Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(ii) formula-NR 35R 36Group, R wherein 35And R 36Be hydrogen atom independently respectively, have the alkyl of 1-2 carbon atom or have the acyl group of 1-2 carbon atom;
R 3Be-(CR 37R 38) x(CR 39R 40) yR 41Group, wherein
X and y are respectively 0 or 1 independently,
R 37, R 38And R 39Be independently respectively:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
R 40Be:
(A) hydrogen atom,
(B) formula-OR 42Group, R wherein 42Be hydrogen atom or alkyl or acyl group with 1-7 carbon atom, or
(C) have the branched-chain or straight-chain alkyl of 1-3 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(D) aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) R 43It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phthalein be base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(a) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(b)-COOH，
(c)-SO 2OH，
(d)-PO(OH) 2，
(e) formula-COOR 44Group, R wherein 44Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(f) formula-NR 45R 46Group, R wherein 45And R 46Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 45And R 46Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(g) formula-CONR 47R 48Group, R wherein 47And R 48Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 47And R 48Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(h) formula-OR 49Group, R wherein 49Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(i) formula-SR 50Group, R wherein 50Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(j) cyano group, or
(k) nitro,
(l) amidino groups of following formula
R wherein 51, R 52And R 53Be respectively hydrogen atom independently or have the alkyl of 1-3 carbon atom and R wherein 51, R 52And R 53In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(m) halogen,
(ii) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 43The single replacement,
(iii) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(iv) formula-COOR 54Group, R wherein 54Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(v) formula-NR 55R 56Group, R wherein 55And R 56Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 55And R 56Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 55And R 56In a group can additionally be radicals R 43,
(vi) formula-CONR 57R 58Group, R wherein 57And R 58Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 57And R 58Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 57And R 58In a group can additionally be radicals R 43,
(vii) formula-COR 59Group, R wherein 59Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 43,
(viii) formula-OR 60Group, R wherein 60Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 43,
(ix) formula-SR 61Group, R wherein 61Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 43,
(x) cyano group,
(xi) nitro, or
(xii) halogen,
R 41Be:
Aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phenol is base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(A) R 62It is aryl, be selected from phenyl, the 2-naphthyl, 2-, 3-, 5-or 6-indyl, 2-or 3-sulfur phenenyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-or 3-furyl, 1-, 2-or 3-pyrryl, 2-, 4-or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4-or 5-oxadiazole base, 1-, 4-or 5-triazolyl, the 2-thiadiazolyl group, 3-or 4-pyridazinyl, the 2-pyrazinyl, the 2-triazinyl, 2-, 3-, 6-or 7-indolizinyl, 2-, 3-, 5-or 6-pseudoindoyl, 2-, 3-, 5-or 6-benzo [b] furyl, 2-, 3-, 5-or 6-benzo [b] sulfur phenenyl, 3-, 5-or 6-indazolyl, 2-, 5-or 6-benzothiazolyl, 2-, 5-or 6-benzimidazolyl-, 2-, 3-, 6-or 7-quinolyl, 3-, 6-or 7-isoquinolyl, 2-or 8-purine radicals, 2-, 3-, 7-or 8-quinolizinyl, 3-, 6-or 7-cinnolinyl, 6-or 7-phenol is base rather, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6-or 7-naphthyridinyl, 2-, 6-or 7-pteridyl and 2-, the group of 6-or 7-quinazolyl
One or more hydrogen atoms of wherein said aryl can randomly and independently be replaced by following groups:
(i) have the branched-chain or straight-chain alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(ii)-COOH，
(iii)-SO 2OH，
(iv)-PO(OH) 2，
(v) formula-COOR 63Group, R wherein 63Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(vi) formula-NR 64R 65Group, R wherein 64And R 65Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 64And R 65Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(vii) formula-CONR 66R 67Group, R wherein 66And R 67Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 66And R 67Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(viii) formula-OR 68Group, R wherein 68Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(ix) formula-SR 69Group, R wherein 69Be hydrogen atom or alkyl, fluoroalkyl or acyl group with 1-7 carbon atom,
(x) cyano group,
(xi) nitro, or
(xii) amidino groups of following formula
R wherein 70, R 71And R 72Be respectively hydrogen atom or alkyl or fluoroalkyl and R wherein independently with 1-3 carbon atom 70, R 71And R 72In two groups can constitute stable hydrocarbon bridge in addition with 3-5 carbon atom, described carbon atom forms heterocycle with nitrogen-atoms therebetween,
(xiii) halogen,
(B) methyl can be replaced by the fluorine atom list or polysubstituted and in addition can be by R 62The single replacement,
(C) have the branched-chain or straight-chain alkyl of 2-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, wherein alkyl or cycloalkyl can be replaced by halogen or oxygen list or be polysubstituted,
(D) formula-COOR 73Group, R wherein 73Be to have the straight or branched alkyl of 1-5 carbon atom or have the cycloalkyl of 3-5 carbon atom,
(E) formula-NR 74R 75Group, R wherein 74And R 75Be hydrogen atom independently respectively, have 1-6 carbon atom alkyl or fluoroalkyl, have the cycloalkyl of 3-6 carbon atom or have the acyl group of 1-7 carbon atom, or R 74And R 75Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 74And R 75In a group can additionally be radicals R 62,
(F) formula-CONR 76R 77Group, R wherein 76And R 77Be hydrogen atom independently respectively, have the alkyl or the fluoroalkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, or R 76And R 77Constitute the stable hydrocarbon bridge with 3-5 carbon atom, described carbon atom forms heterocycle and R wherein with therebetween nitrogen-atoms 76And R 77In a group can additionally be radicals R 62,
(G) formula-COR 78Group, R wherein 78Be hydrogen atom, have the straight or branched alkyl of 1-5 carbon atom, cycloalkyl or a R with 3-5 carbon atom 62,
(H) formula-OR 79Group, R wherein 79Be hydrogen atom, have alkyl, fluoroalkyl or the acyl group of 1-7 carbon atom or a R 62,
(I) formula-SR 80Group, R wherein 80Be hydrogen atom, have alkyl, fluoroalkyl or acyl group or a R of 1-7 carbon atom 62,
(J) cyano group,
(K) nitro, or
(L) halogen,
R 4Be Cl or trifluoromethyl; With,
R 5And R 6Be respectively hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl independently.
17. contain the pharmaceutical composition of pharmaceutically acceptable carrier and claim 2,3,4,5,6,7,8,9 or 10 compound.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103534252A (en) * 2011-04-08 2014-01-22 上海艾力斯医药科技有限公司 Benzomorpholine derivatives, preparation method and use thereof
CN104447603A (en) * 2004-07-02 2015-03-25 默沙东公司 CETP inhibitors
WO2022199289A1 (en) * 2021-03-22 2022-09-29 中国药科大学 Novel androgen receptor degrader, preparation method, and medical use

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US20080050367A1 (en) 1998-04-07 2008-02-28 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
US6043376A (en) * 1998-08-06 2000-03-28 Boehringer Ingelheim Pharmaceuticals, Inc. Synthesis of alpha-methyl, alpha-substituted amino acids
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US6110922A (en) 1998-12-29 2000-08-29 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US6492408B1 (en) 1999-07-21 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
US6414153B1 (en) 1999-07-21 2002-07-02 Boehringer Ingelheim Pharmaceuticals, Inc. 1-phenylpydrrolidin-2-ones and -thiones and 1-(4-pyridyl)pydrrolidin-2-ones and -thiones which are useful in the treatment of inflammatory disease
WO2001007052A1 (en) 1999-07-21 2001-02-01 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
WO2001007044A1 (en) 1999-07-21 2001-02-01 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
US6897225B1 (en) 1999-10-20 2005-05-24 Tanabe Seiyaku Co., Ltd. Inhibitors of αLβ2 mediated cell adhesion
NZ523445A (en) 2000-06-29 2004-10-29 Abbott Lab Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
US6846643B2 (en) * 2000-08-14 2005-01-25 Boehringer Ingelheim Pharmaceuticals, Inc. Methods and molecules useful for identifying molecules that bind LFA-1 and for determining receptor occupancy
WO2002044181A1 (en) * 2000-12-01 2002-06-06 Bristol-Myers Squibb Company Hydantoin compounds useful as anti-inflammatory agents
WO2002050080A1 (en) * 2000-12-19 2002-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
BR0214437A (en) 2001-11-30 2004-10-13 Lilly Co Eli Compound, pharmaceutical composition, methods of modulating a peroxisome proliferator-activated receptor, treating and preventing diabetes mellitus, and treating syndrome x, and cardiovascular disease in a mammal, and, use of a compound
TW200303200A (en) 2002-02-07 2003-09-01 Tanabe Seiyaku Co Inhibitors of α L β 2 integrin mediated cell adhesion
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
JP4617449B2 (en) 2002-07-11 2011-01-26 ヴィキュロン ファーマシューティカルズ インコーポレイテッド N-hydroxyamide derivative having antibacterial activity
US6974815B2 (en) 2002-10-11 2005-12-13 Bristol-Myers Squibb Company Hexahydro-benzimidazolone compounds useful as anti-inflammatory agents
US6852748B1 (en) 2002-10-30 2005-02-08 Boehringer Ingelheim Pharmaceuticals, Inc. Derivatives of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide
US6844360B2 (en) 2002-10-30 2005-01-18 Boehringer Ingelheim Pharmaceuticals, Inc. Derivatives of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonylamino]-propionamide
US7354933B2 (en) 2003-01-31 2008-04-08 Aventis Pharma Sa Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
FR2850652B1 (en) * 2003-01-31 2008-05-30 Aventis Pharma Sa NOVEL CYCLIC UREA DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF KINASES
PL2384753T3 (en) * 2003-08-29 2016-09-30 Hydantoin derivatives as inhibitors of cellular necrosis
US7199125B2 (en) 2003-10-02 2007-04-03 Bristol-Myers Squibb Company Spiro-cyclic compounds useful as anti-inflammatory agents
AU2005275213A1 (en) * 2004-07-16 2006-02-23 Schering Corporation Hydantoin derivatives for the treatment of inflammatory disorders
WO2006014828A1 (en) * 2004-07-27 2006-02-09 Boehringer Ingelheim International, Gmbh Synthesis of 6,7-dihydro-5h-imidazo[1,2-a]imidazole-3-sulfonic acid amides
EP1621535A1 (en) * 2004-07-27 2006-02-01 Aventis Pharma S.A. Substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
US7375237B2 (en) 2004-08-18 2008-05-20 Bristol-Myers Squibb Company Pyrrolizine compounds useful as anti-inflammatory agents
TW200616634A (en) 2004-10-01 2006-06-01 Bristol Myers Squibb Co Crystalline forms and process for preparing spiro-hydantoin compounds
JPWO2006051937A1 (en) * 2004-11-15 2008-05-29 塩野義製薬株式会社 Hetero 5-membered ring derivatives
US7186727B2 (en) 2004-12-14 2007-03-06 Bristol-Myers Squibb Company Pyridyl-substituted spiro-hydantoin compounds and use thereof
WO2006066089A1 (en) 2004-12-15 2006-06-22 Neuralab Limited Humanized amyloid beta antibodies for use in improving cognition
CN101166743A (en) 2005-05-19 2008-04-23 贝林格尔·英格海姆国际有限公司 Derivatives of 6,7-dihydro-5H-imidazo[1,2-alpha] imidazole-3-sulfonic acid
WO2007047146A2 (en) * 2005-10-11 2007-04-26 Intermune, Inc. Inhibitors of viral replication
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8168667B2 (en) 2006-05-31 2012-05-01 Galapagos Nv Imidazolidine derivatives, uses therefor, preparation thereof and compositions comprising such
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
PL2182983T3 (en) 2007-07-27 2014-10-31 Janssen Alzheimer Immunotherap Treatment of amyloidogenic diseases with humanised anti-abeta antibodies
JO3076B1 (en) 2007-10-17 2017-03-15 Janssen Alzheimer Immunotherap Immunotherapy regimes dependent on apoe status
DK2225238T3 (en) 2007-11-29 2014-11-24 Boehringer Ingelheim Int Derivatives of 6,7-dihydro-5H-imidazoý1,2- imidazol-3-carboxylic acid amides.
GB2463514C (en) 2008-09-11 2018-09-26 Galapagos Nv Imidazolidine compounds and uses therefor
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
CA2772760A1 (en) 2008-12-23 2010-07-01 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
ITBO20090078A1 (en) * 2009-02-13 2010-08-14 Consiglio Nazionale Ricerche COMPOUNDS FOR TREATING TUMOR TO THE PROSTATE AND PROCEDURES FOR THEIR SYNTHESIS
MX2011012717A (en) 2009-06-02 2011-12-14 Boehringer Ingelheim Int DERIVATIVES OF 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLI C ACID AMIDES.
US8481750B2 (en) 2009-06-02 2013-07-09 Boehringer Ingelheim International Gmbh Derivatives of 6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid amides
US20160024098A1 (en) 2013-03-15 2016-01-28 President And Fellows Of Harvard College Hybrid necroptosis inhibitors
KR20170012360A (en) * 2014-06-12 2017-02-02 알로사이트 파마수티컬스 아게 Small molecule lfa-1 inhibitors
AR102942A1 (en) 2014-12-11 2017-04-05 Bayer Cropscience Ag DERIVATIVES OF ARILSULFIDE AND ARILSULPHOXIDE OF FIVE C-N-CONNECTED MEMBERS, AS PESTICIDES
CA2970525A1 (en) 2014-12-11 2016-06-16 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2015493A1 (en) * 1968-08-12 1970-04-30 Sumitomo Chemical Co
DK123717B (en) * 1968-11-25 1972-07-24 Sumitomo Chemical Co 3- (3 ', 5'-Dihalophenyl) -imidazolidine-2,4-dione derivatives with mirobicidal action.
EP0091596B1 (en) * 1982-04-08 1991-09-11 Shell Internationale Researchmaatschappij B.V. Hydantoins, their preparation and application
IE940525L (en) * 1988-05-25 1989-11-25 Warner Lambert Co Known and selected novel arylmethylenyl derivatives of¹thiazolidinones, imidazolidinones and oxazolidinones useful¹as antiallergy agents and antiinflammatory agents
EP0545478A1 (en) * 1991-12-03 1993-06-09 MERCK SHARP & DOHME LTD. Heterocyclic compounds as tachykinin antagonists
TW521073B (en) * 1994-01-05 2003-02-21 Hoechst Marion Roussel Inc New optionally substituted phenylimidazolidines, their preparation process, their use as anti-androgenic agent and the pharmaceutical compositions containing them

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447603A (en) * 2004-07-02 2015-03-25 默沙东公司 CETP inhibitors
CN103534252A (en) * 2011-04-08 2014-01-22 上海艾力斯医药科技有限公司 Benzomorpholine derivatives, preparation method and use thereof
CN103534252B (en) * 2011-04-08 2016-08-24 上海艾力斯医药科技有限公司 Benzomorpholine derivatives and its preparation method and application
WO2022199289A1 (en) * 2021-03-22 2022-09-29 中国药科大学 Novel androgen receptor degrader, preparation method, and medical use

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